Brugada Syndrome and Pulmonary Atresia with Intact Interventricular Septum: Fortuitous Finding or New Genetic Connection?

Brugada syndrome is a rare arrhythmogenic syndrome associated mainly with pathogenic variants in the SCN5A gene. Right ventricle outflow tract fibrosis has been reported in some cases of patients diagnosed with Brugada syndrome. Pulmonary atresia with an intact ventricular septum is characterized by the lack of a functional pulmonary valve, due to the underdevelopment of the right ventricle outflow tract. We report, for the first time, a 4-year-old boy with pulmonary atresia with an intact ventricular septum who harbored a pathogenic de novo variant in SCN5A, and the ajmaline test unmasked a type-1 Brugada pattern. We suggest that deleterious variants in the SCN5A gene could be implicated in pulmonary atresia with an intact ventricular septum embryogenesis, leading to overlapping phenotypes.

Partial replacement of mineral fertilisers with animal manures in an apple orchard: Effects on GHG emission.

Partial replacement of mineral fertilisers (MF) with animal manures is a good alternative to reduce MF use and increase both nutrient cycling in agriculture and soil organic matter. However, the adoption of this practice must not lead to increased environmental impacts. In this two-year study conducted in an apple orchard, MF were partially replaced with various animal manures, including cattle slurry (CS), acidified cattle slurry (ACS), solid cattle manure (CsM), or poultry manure (PM), and their impacts on greenhouse gas emission (GHG: CO2, N2O and CH4) were examined. A control (CTRL) receiving only MF served as the baseline, representing the conventional scenario in orchard fertilisation. Overall, replacing MF with manures increased GHG emissions, with the magnitude of the impacts depending on the specific characteristics of the manures and the amount of nutrients and organic matter applied. Comparing to the CTRL, application of ACS and CS led to higher CH4 and N2O emissions, while PM application increased both N2O and CO2 emissions. In contrast, replacement with PM and CsM decreased CH4 emissions. Nevertheless, results varied between the two years, influenced by several factors, including soil conditions. While acidification showed potential to mitigate CH4 emissions, it also led to increased N2O emissions compared to CS, particularly in 2022, suggesting the need for further investigation to avoid emission trade-offs. Replacement with CS (20.49 t CO2-eq ha-1) and CsM (20.30 t CO2-eq ha-1) showed comparable global warming potential (GWP) to the conventional scenario (CTRL, 19.49 t CO2-eq ha-1), highlighting their potential as viable MF substitutes.

Prenatal diagnosis of coarctation: Impact on early and late cardiovascular outcome.

BACKGROUND: Prenatal diagnosis (PND) of aortic coarctation (AoCo) has been associated with a significant improvement in early results, but there is limited information on the long-term cardiovascular outcome. METHODS: We studied 103 patients with simple AoCo, operated in the neonatal period, with a median follow-up of 8,5 years (2 to 23,7 years), with 47% followed for over 10 years. PND was made in 35%. The primary aim was to determine the short and long-term cardiovascular impact of PND of AoCo. RESULTS: Neonates with PND had less preoperative neonatal complications, with only 2,8% incidence of a composite preoperative severe morbidity course, compared to 28% in the postnatal group. PND patients underwent surgery 8 days earlier and had a shorter length of stay in ICU. PND did not impact the incidence of post-operative complications. On the long-term, prevalence of hypertension, left ventricular hypertrophy and rate of recoarctation were not influenced by PND. The PND group had mean 24 h diastolic BP 9 mmHg lower and mean daytime diastolic BP 11 mmHg lower. In the final multivariable model, PND was the single independent variable correlating with daytime diastolic BP. CONCLUSION: PND of AoCo effectively leads to a better pre-operative course with less pre-operative morbidity. We found no significant differences in immediate post-operative cardiovascular outcomes. A better initial course of patients with PND does not have a major long-term impact on cardiovascular outcomes, nevertheless, at late follow-up PND patients had lower diastolic BP values on ambulatory monitoring, which may have an impact on long-term cardiovascular risk.

Digestive glycosidases from cannonball jellyfish (Stomolophus sp. 2): identification and temporal-spatial variability.

Jellyfish are economically important organisms in diverse countries, carnivorous organisms that consume various prey (crustaceans, mollusks, bivalves, etc.) and dissolved carbohydrates in marine waters. This study was focused on detecting and quantifying the activity of digestive glycosidases from the cannonball jellyfish (Stomolophus sp. 2) to understand carbohydrate digestion and its temporal-spatial variation. Twenty-three jellyfish gastric pouches were collected in 2015 and 2016 in the Gulf of California in three localities (Las Guásimas, Hermosillo, and Caborca). Nine samples were in intra-localities from Las Guásimas. Chitinase (Ch), ß-glucosidase (ß-glu), and ß-N-acetylhexosaminidase (ß-NAHA) were detected in the gastric pouches. However, cellulase, exoglucanase, α-amylase, polygalacturonase, xylanase, and κ-carrageenase were undetected. Detected enzymes showed halotolerant glycolytic activity (i = 0-4 M NaCl), optimal pH, and temperature at 5.0 and 30-50 °C, respectively. At least five ß-glucosidase and two ß-N-acetylhexosaminidase were detected using zymograms; however, the number of proteins with chitinase activity is not precise. The annual variation of cannonball jellyfish digestive glycosidases from Las Guásimas between 2015-2016 does not show significant differences despite the difference in phytoplankton measured as chlorophyll α (1.9 and 3.4 mg/m3, respectively). In the inter-localities, the glycosidase activity was statistically different in all localities, except for ß-N-acetylhexosaminidase activity between Caborca and Hermosillo (3,009.08 ± 87.95 and 3,101.81 ± 281.11 mU/g of the gastric pouch, respectively), with chlorophyll α concentrations of 2.6, 3.4 mg/m3, respectively. For intra-localities, the glycosidase activity did not show significant differences, with a mean chlorophyll α of 1.3 ± 0.1 mg/m3. These results suggest that digestive glycosidases from Stomolophus sp. 2 can hydrolyze several carbohydrates that may belong to their prey or carbohydrates dissolved in marine waters, with salinity over ≥ 0.6 M NaCl and diverse temperature (4-80 °C) conditions. Also, chlorophyll α is related to glycosidase activity in both seasons and inter-localities, except for chitinase activity in an intra-locality (Las Guásimas).

Diastolic Function and Left Atrial Strain in Young Patients with History of Aortic Coarctation Repair.

Aortic coarctation (AoCo) leads to long-term sequelae that may impair heart function. Data regarding new echocardiographic function parameters such as atrial strain, in affected patients, are scarce. This study aims to describe these parameters in AoCo patients and define their association with severity measures. 53 AoCo patients and 31 healthy controls, aged 12-40 years, were evaluated. Effectively corrected AoCo (cAoCo) was defined as aortic trans-isthmic corrected Doppler gradient (Dgrad) ≤ 20 mmHg (n = 36), and recoarctation (rAoCo) as Dgrad > 20 mmHg (n = 17). Dependent variables were: E/E'; atrial reservoir strain (Ares); and atrial conduit strain (Acd). T-tests/Mann-Whitney U tests were used to compare these among groups. Multivariable regression was used to test correlation with systolic blood pressure (SBP), indexed LV mass (ILVM), Dgrad, and the ratio between the narrowest diameter of aortic arch and aorta at diaphragm level (Aoratio). In cAoCo and rAoCo patients, E/E' was higher (p < 0.001), Ares, and Acd were lower (p < 0.001 for both) comparing with controls. Acd was higher in cAoCo than rAoCo (p = 0.045). Higher Ares was associated with higher Aoratio (p = 0.002), and lower Acd with higher Dgrad (0.014). EF and GLS were not different among groups. Young patients with effectively corrected aortic coarctation have persistent changes in diastolic function parameters (E/E' and atrial strain), and these are affected by anatomical sequelae. These patients' physiology is closer to patients with recoarctation, than to healthy individuals. This provides rationale for a stronger prevention, and treatment, of arterial dysfunction and high left ventricular afterload in these patients.

Azacitidine-induced massive pericardial effusion in a child with myelodysplastic syndrome.

INTRODUCTION: Pericardial effusions are rare yet potentially fatal conditions in children. Azacitidine is a DNA-hypomethylating agent used in the treatment of myelodysplastic syndrome. Although seldomly described in adults, no cases of azacitidine-induced pericardial effusion have been reported in children. CASE REPORT: A 7-year-old boy with myelodysplastic syndrome presented with a large pericardial effusion with risk for cardiac tamponade after his first azacitidine cycle. MANAGEMENT & OUTCOME: The patient was admitted to a pediatric ICU, antibiotic and steroid therapy were initiated. Pericardiocentesis was done due to hemodynamic instability. Serum and pericardial fluid complementary evaluation excluded infectious and malignant causes. The pericardial effusion did not reappear and additional pleural and ascitic slight effusions responded well to diuretics. Follow-up azacitidine cycles were administered by tapering daily dosages and using adjunctive steroid therapy, with no additional adverse events. DISCUSSION: We report the first pediatric case of large pericardial effusion secondary to azacitidine therapy in a child with MDS. This adverse reaction has not been described in pediatric patients, in which this therapeutic option has been increasingly used. We seek to raise awareness on the potential life-threatening cardiotoxicity of azacitidine in pediatric patients.

Accelerated idioventricular rhythm in a healthy newborn: frightening but non-threatening.

Accelerated idioventricular rhythm is a rare but benign form of ventricular tachycardia which might be challenging to differentiate from other more worrisome forms. We present the case of a healthy newborn diagnosed with an accelerated idioventricular rhythm which is spontaneously terminated without the need for medical therapy.

Double aortic arch: an elusive diagnosis in a child with CHD.

An 18-month-old male with pulmonary atresia and ventricular septal defect presented with stridor after neonatal systemic-to-pulmonary artery shunt surgery, that persisted on follow-up. CT angiography revealed a vascular ring with balanced double aortic arch.

Viability of the vaquita, Phocoena sinus (Cetacea: Phocoenidae) population, threatened by poaching of Totoaba macdonaldi (Perciformes: Sciaenidae) / Viabilidad de la población de vaquita marina, Phocoena sinus (Cetacea: Phocoenidae), amenazada por la pesca ilegal de Totoaba macdonaldi (Perciformes: Sciaenidae)

Abstract Introduction: Despite extensive science-based conservation policy recommendations, with fewer than 20 individuals remaining, the vaquita (Phocoena sinus) -endemic to the Gulf of California- is the world's most endangered marine mammal due to incidental catch in fishing nets and whether it can recover is unclear. Objective: Assess expectations for vaquita over the next two decades. Methods: We identified factors affecting the vaquita, constructed life tables, derived demographic parameters for different scenarios and conducted a population viability analysis using stochastic age-structured matrix Leslie models. Results: Analytical results indicate that the vaquita net growth rate is particularly sensitive to juvenile survival. We find that intensive, ongoing bycatch in gillnets used to poach totoaba (Totoaba macdonaldi) over the past decade brought the vaquita population to its current critically low size. Currently this seems to be exacerbated by demographic stochasticity and a potential Allee effect. Conclusions: If totoaba poaching is eliminated immediately, demographically, vaquita can recover; its long-term survival will depend on its uncertain genetic status, although a recent study found encouraging results in this regard.

Resumen Introducción: Pese a las acciones de conservación basadas en la ciencia y las políticas recomendadas, con menos de 20 individuos sobrevivientes, la vaquita (Phocoena sinus) -endémica del Golfo de California- es el mamífero marino más amenazado del mundo debido a su muerte incidental en redes de pesca; una pregunta relevante es si su población se puede recuperar. Objetivo: Evaluar las expectativas para la vaquita marina durante los próximos 20 años. Métodos: Identificamos los factores que afectan a la vaquita marina, construimos tablas de vida, derivamos parámetros demográficos para diferentes escenarios y realizamos un análisis de viabilidad poblacional utilizando matrices estocásticas de Leslie, estructuradas por edad. Resultados: La tasa de crecimiento neto de la vaquita es muy sensible a la supervivencia de los juveniles. Encontramos que la captura incidental intensiva y continua en redes de enmalle para la pesca furtiva de totoaba (Totoaba macdonaldi) durante la última década llevó a la población de vaquitas a su actual estado crítico. Esto parece agravarse por la estocasticidad demográfica y un potencial efecto Allee. Conclusiones: Si la pesca furtiva de totoaba se elimina de inmediato, demográficamente la vaquita puede recuperarse; su supervivencia a largo plazo dependerá de su incierto estatus genético, aunque los resultados de un estudio reciente son alentadores en este sentido.

Illegal fisheries, environmental crime, and the conservation of marine resources.

The illegal harvest of marine species within exclusive economic zones can have a strong impact on the function of local ecosystems and livelihoods of coastal communities. The complexity of these problems is often overlooked in the development of solutions, leading to ineffective and sometimes harmful social and environmental outcomes. One-dimensional, oversimplified perspectives can lead to conservation prescriptions that exacerbate social stressors. This is particularly critical in the case of international illegal trade of endangered, high-value species, which generate a value chain in which artisanal fishers are the first operational and often the weakest link of an intricate web. We examined 2 illegal fisheries, totoaba (Totoaba macdonaldi) and sea cucumber (Isostichopus badionotus and Holothuria floridana), in Mexico. Although these are 2 separate and independent fisheries, important ecological (resource condition, fishery impacts at the ecosystem level) and social (governance, markets) similarities improve understanding of their complexity. Our findings are relevant globally and show the need for interdisciplinary decision-making groups, community engagement, and the development of demand reduction measures.

Pesquerías Ilegales, Crímenes Ambientales y la Conservación de los Recursos Marinos Resumen La cosecha ilegal de especies marinas dentro de las zonas económicas exclusivas puede tener un impacto serio sobre la función de los ecosistemas locales y el economia de las comunidades costeras. La complejidad de estos problemas generalmente se ignora durante el desarrollo de soluciones, lo que conlleva a resultados ambientales y sociales poco efectivos y algunas veces dañinos. Las perspectivas unidimensionales y sobresimplificadas pueden derivar en prescripciones de conservación que empeoran las condiciones sociales sociales. Lo anterior es particularmente crítico para el caso del mercado ilegal de especies en peligro y de alto valor, lo que genera una cadena de valores en la que los pescadores tradicionales son el primer eslabón operativo y con frecuencia el más débil de una red intrincada. Examinamos dos pesquerías ilegales, la de la totoaba (Totoaba macdonaldi) y la del pepino de mar (Isostichopus badionotus y Holothuria floridana), en México. Aunque estas dos pesquerías son diferentes e independientes, las importantes similitudes ecológicas (estado del recurso, impactos de la pesquería a nivel de ecosistema) y sociales (governancia, mercados) mejoran el conocimiento de su complejidad. Nuestros hallazgos son relevantes a escala global y muestran la necesidad de tener grupos interdisciplinarios para tomar decisiones, la participación de la comunidad y el desarrollo de medidas para reducir la demanda por el producto pesquero.

Sinus node disfunction in an adolescent with systemic lupus erythematosus.

Cardiac involvement in systemic lupus erythematosus (SLE) is well documented. The pericardium, myocardium and endocardium, as well as the coronary arteries, the valves and the conduction system can all be affected. While pericarditis is common, arrythmias are less frequently described.We present a 13-year-old male, who had fatigue, anorexia, weight loss, myalgias and arthralgias for four months. On physical examination, we identified bradycardia (heart rate 31-50 bpm), oral and nasal ulcers and polyarthritis. The laboratory results showed hemolytic anemia, hypocomplementemia, antinuclear and anti-dsDNA antibodies, hematuria and non-nephrotic proteinuria. Renal function was normal. Lupus nephritis class II was diagnosed by kidney biopsy. On the transthoracic echocardiogram we identified a minimal pericardial effusion, suggesting pericarditis, and, on the electrocardiogram, we detected sinus arrest with junctional rhythm, denoting sinus node dysfunction. The patient was diagnosed with juvenile SLE with cardiac, renal, musculoskeletal and hematologic involvement. Disease remission and cardiac rhythm control were obtained with steroids and mycophenolate mofetil. Currently, the patient is asymptomatic, with normal sinus rhythm.We described an adolescent with SLE who had sinus node dysfunction upon diagnosis. Other cases have been reported in adults but none in juvenile SLE. All SLE patients should have a thorough cardiac examination to promptly diagnose and treat the innumerous cardiac manifestations of this disease.

The future of food from the sea.

Global food demand is rising, and serious questions remain about whether supply can increase sustainably1. Land-based expansion is possible but may exacerbate climate change and biodiversity loss, and compromise the delivery of other ecosystem services2-6. As food from the sea represents only 17% of the current production of edible meat, we ask how much food we can expect the ocean to sustainably produce by 2050. Here we examine the main food-producing sectors in the ocean-wild fisheries, finfish mariculture and bivalve mariculture-to estimate 'sustainable supply curves' that account for ecological, economic, regulatory and technological constraints. We overlay these supply curves with demand scenarios to estimate future seafood production. We find that under our estimated demand shifts and supply scenarios (which account for policy reform and technology improvements), edible food from the sea could increase by 21-44 million tonnes by 2050, a 36-74% increase compared to current yields. This represents 12-25% of the estimated increase in all meat needed to feed 9.8 billion people by 2050. Increases in all three sectors are likely, but are most pronounced for mariculture. Whether these production potentials are realized sustainably will depend on factors such as policy reforms, technological innovation and the extent of future shifts in demand.

Fisheries governance in the face of climate change: Assessment of policy reform implications for Mexican fisheries.

Climate change is driving shifts in the abundance and distribution of marine fish and invertebrates and is having direct and indirect impacts on seafood catches and fishing communities, exacerbating the already negative effects of unsustainably high fishing pressure that exist for some stocks. Although the majority of fisheries in the world are managed at the national or local scale, most existing approaches to assessing climate impacts on fisheries have been developed on a global scale. It is often difficult to translate from the global to regional and local settings because of limited relevant data. To address the need for fisheries management entities to identify those fisheries with the greatest potential for climate change impacts, we present an approach for estimating expected climate change-driven impacts on the productivity and spatial range of fisheries at the regional scale in a data-poor context. We use a set of representative Mexican fisheries as test cases. To assess the implications of climate impacts, we compare biomass, harvest, and profit outcomes from a bioeconomic model under contrasting management policies and with and without climate change. Overall results show that climate change is estimated to negatively affect nearly every fishery in our study. However, the results indicate that overfishing is a greater threat than climate change for these fisheries, hence fixing current management challenges has a greater upside than the projected future costs of moderate levels of climate change. Additionally, this study provides meaningful first approximations of potential effects of both climate change and management reform in Mexican fisheries. Using the climate impact estimations and model outputs, we identify high priority stocks, fleets, and regions for policy reform in Mexico in the face of climate change. This approach can be applied in other data-poor circumstances to focus future research and policy reform efforts on stocks now subject to additional stress due to climate change. Considering their growing relevance as a critical source of protein and micronutrients to nourish our growing population, it is urgent for regions to develop sound fishery management policies in the short-term as they are the most important intervention to mitigate the adverse effects of climate change on marine fisheries.

Review of California sea lion (Zalophus californianus) abundance, and population dynamics in the Gulf of California

Introduction: The life history of the California sea lion (Zalophus californianus) in the Gulf of California is marked by a series of important events influencing and modifying its population growth, distribution, and evolution. Despite the fact that this population has been studied since the 1950s, research has been rather punctual and fragmentary. Before 2010, there are only a few surveys conducted simultaneously in all rookeries, thus there is no reliable information on key aspects of life cycle, population trend and potential threats. In the present work we conducted a review of California sea lion life history and environmental changes in the Gulf of California thorough a collation survey data encompassing the last 37 years. Objective: Our aim was focused on identifying short- and long-term processes potentially acting on the population, and hopefully improve knowledge about the population trend and status using different points of view. Methods: We collected and analyzed population survey data from different sources since the 1970s to 2018: published papers, master's and doctoral thesis, in addition to technical reports. The survey data are organized in sections corresponding with crucial population life history events. Results: Considering a long-time period the population size appears to be stable with zero growth. Cyclic interannual fluctuation seem to denote a certain dependence with climatic factors, not directly with El Niño, but with sea surface temperature anomalies that determine prey availability. However, many doubts persist about the incidence of different local environmental factors on gender and age, particularly related with juvenile recruitment and female survival rate. Conclusions: In conclusion, more information is required based on seasonal surveys, life cycle, regional environmental variation. Statistical errors need to be assessed and monitoring methods should be standardized and must be considered to ascertain short- and long-term population and colony spatial-temporal patterns.

Introducción: El lobo marino de California (Zalophus californianus) en el Golfo de California se caracteriza por una serie de eventos que influyen en el crecimiento, evolución y distribución de la población. Los estudios poblacionales iniciaron en 1950, aunque las investigaciones fueron puntuales y fragmentadas. Antes de 2010 existen pocos censos simultáneos de las 13 colonias de lobos marinos, con los cuales se obtuvo información sobre el ciclo de vida, la tendencia poblacional y las potenciales amenazas de estos organismos. Objetivo: En esta investigación se presenta un resumen de 37 años de historia de investigaciones del lobo marino de California y del ecosistema del Golfo de California. Métodos: Se realizó un análisis de los procesos de corto y largo plazo que actúan sobre la población, revelando aspectos poco conocidos. Se recolectaron y analizaron datos para el periodo de 1970 al 2018: artículos, tesis de posgrado y reportes técnicos, que fueron organizados en secciones relacionadas con eventos ambientales cruciales para la población. Resultados: A largo plazo, la población parece estar estable y presenta fluctuaciones interanuales cíclicas que evidencian dependencia con factores climáticos como anomalías de temperatura superficial del mar regional que determinan un cambio en la disponibilidad de presas para los lobos marinos. No es claro el posible efecto que factores ambientales locales puedan ocasionar en las diferentes clases de edad y por sexos, en particular sobre el reclutamiento de juveniles y la tasa de supervivencia de las hembras. Conclusiones: El presente trabajo identifica las prioridades de información para esta población y ofrece recomendaciones como el monitoreo estandarizado y la consideración de variaciones espacio-temporales locales.

An RNA-centric dissection of host complexes controlling flavivirus infection.

Flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), cause severe human disease. Co-opting cellular factors for viral translation and viral genome replication at the endoplasmic reticulum is a shared replication strategy, despite different clinical outcomes. Although the protein products of these viruses have been studied in depth, how the RNA genomes operate inside human cells is poorly understood. Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), we took an RNA-centric viewpoint of flaviviral infection and identified several hundred proteins associated with both DENV and ZIKV genomic RNA in human cells. Genome-scale knockout screens assigned putative functional relevance to the RNA-protein interactions observed by ChIRP-MS. The endoplasmic-reticulum-localized RNA-binding proteins vigilin and ribosome-binding protein 1 directly bound viral RNA and each acted at distinct stages in the life cycle of flaviviruses. Thus, this versatile strategy can elucidate features of human biology that control the pathogenesis of clinically relevant viruses.

A metadata approach to evaluate the state of ocean knowledge: Strengths, limitations, and application to Mexico.

Climate change, mismanaged resource extraction, and pollution are reshaping global marine ecosystems with direct consequences on human societies. Sustainable ocean development requires knowledge and data across disciplines, scales and knowledge types. Although several disciplines are generating large amounts of data on marine socio-ecological systems, such information is often underutilized due to fragmentation across institutions or stakeholders, limited standardization across scale, time or disciplines, and the fact that information is often not searchable within existing databases. Compiling metadata, the information which describes existing sets of data, is an effective tool that can address these challenges, particularly when metadata corresponding to multiple datasets can be combined to integrate, organize and classify multidisciplinary data. Here, using Mexico as a case study, we describe the compilation and analysis of a metadatabase of ocean knowledge that aims to improve access to information, facilitate multidisciplinary data sharing and integration, and foster collaboration among stakeholders. We also evaluate the knowledge trends and gaps for informing ocean management. Analysis of the metadatabase highlights that past and current research in Mexico focuses strongly on ecology and fisheries, with biological data more consistent over time and space compared to data on human dimensions. Regional imbalances in available information were also evident, with most available information corresponding to the Gulf of California, Campeche Bank and Caribbean and less available for the central and south Pacific and the western Gulf of Mexico. Despite existing knowledge gaps in Mexico and elsewhere, we argue that systematic efforts such as this can often reveal an abundance of information for decision-makers to develop policies that meet key commitments on ocean sustainability. Surmounting current cross-scale social and ecological challenges for sustainability requires transdisciplinary approaches. Metadatabases are critical tools to make efficient use of existing data, highlight and address strengths and deficiencies, and develop scenarios to inform policies for managing complex marine social-ecological systems.

Impact of a patient-derived hepatitis C viral RNA genome with a mutated microRNA binding site.

Hepatitis C virus (HCV) depends on liver-specific microRNA miR-122 for efficient viral RNA amplification in liver cells. This microRNA interacts with two different conserved sites at the very 5' end of the viral RNA, enhancing miR-122 stability and promoting replication of the viral RNA. Treatment of HCV patients with oligonucleotides that sequester miR-122 resulted in profound loss of viral RNA in phase II clinical trials. However, some patients accumulated in their sera a viral RNA genome that contained a single cytidine to uridine mutation at the third nucleotide from the 5' genomic end. It is shown here that this C3U variant indeed displayed higher rates of replication than that of wild-type HCV when miR-122 abundance is low in liver cells. However, when miR-122 abundance is high, binding of miR-122 to site 1, most proximal to the 5' end in the C3U variant RNA, is impaired without disrupting the binding of miR-122 to site 2. As a result, C3U RNA displays a much lower rate of replication than wild-type mRNA when miR-122 abundance is high in the liver. This phenotype was accompanied by binding of a different set of cellular proteins to the 5' end of the C3U RNA genome. In particular, binding of RNA helicase DDX6 was important for displaying the C3U RNA replication phenotype in liver cells. These findings suggest that sequestration of miR-122 leads to a resistance-associated mutation that has only been observed in treated patients so far, and raises the question about the function of the C3U variant in the peripheral blood.

ciRS-7 exonic sequence is embedded in a long non-coding RNA locus.

ciRS-7 is an intensely studied, highly expressed and conserved circRNA. Essentially nothing is known about its biogenesis, including the location of its promoter. A prevailing assumption has been that ciRS-7 is an exceptional circRNA because it is transcribed from a locus lacking any mature linear RNA transcripts of the same sense. To study the biogenesis of ciRS-7, we developed an algorithm to define its promoter and predicted that the human ciRS-7 promoter coincides with that of the long non-coding RNA, LINC00632. We validated this prediction using multiple orthogonal experimental assays. We also used computational approaches and experimental validation to establish that ciRS-7 exonic sequence is embedded in linear transcripts that are flanked by cryptic exons in both human and mouse. Together, this experimental and computational evidence generates a new model for regulation of this locus: (a) ciRS-7 is like other circRNAs, as it is spliced into linear transcripts; (b) expression of ciRS-7 is primarily determined by the chromatin state of LINC00632 promoters; (c) transcription and splicing factors sufficient for ciRS-7 biogenesis are expressed in cells that lack detectable ciRS-7 expression. These findings have significant implications for the study of the regulation and function of ciRS-7, and the analytic framework we developed to jointly analyze RNA-seq and ChIP-seq data reveal the potential for genome-wide discovery of important biological regulation missed in current reference annotations.

Influenza virus differentially activates mTORC1 and mTORC2 signaling to maximize late stage replication.

Influenza A virus usurps host signaling factors to regulate its replication. One example is mTOR, a cellular regulator of protein synthesis, growth and motility. While the role of mTORC1 in viral infection has been studied, the mechanisms that induce mTORC1 activation and the substrates regulated by mTORC1 during influenza virus infection have not been established. In addition, the role of mTORC2 during influenza virus infection remains unknown. Here we show that mTORC2 and PDPK1 differentially phosphorylate AKT upon influenza virus infection. PDPK1-mediated phoshorylation of AKT at a distinct site is required for mTORC1 activation by influenza virus. On the other hand, the viral NS1 protein promotes phosphorylation of AKT at a different site via mTORC2, which is an activity dispensable for mTORC1 stimulation but known to regulate apoptosis. Influenza virus HA protein and down-regulation of the mTORC1 inhibitor REDD1 by the virus M2 protein promote mTORC1 activity. Systematic phosphoproteomics analysis performed in cells lacking the mTORC2 component Rictor in the absence or presence of Torin, an inhibitor of both mTORC1 and mTORC2, revealed mTORC1-dependent substrates regulated during infection. Members of pathways that regulate mTORC1 or are regulated by mTORC1 were identified, including constituents of the translation machinery that once activated can promote translation. mTORC1 activation supports viral protein expression and replication. As mTORC1 activation is optimal midway through the virus life cycle, the observed effects on viral protein expression likely support the late stages of influenza virus replication when infected cells undergo significant stress.

Influencia de la proporción sexual y del ambiente en la tasa de crecimiento poblacional de Callinectes bellicosus (Decapoda: Portunidae) del Golfo de California / Sex ratio and environmental influence on population growth rate of Callinectes bellicosus (Decapoda: Portunidae) in the Gulf of California

ResumenPara la jaiba café (Callinectes bellicosus) capturada en Sonora, México dentro del Golfo de California desde 1986, durante 20 años se ha observado una tendencia decreciente en la biomasa. Se estimaron las tasas de crecimiento poblacional (r) y proporción de sexos de C. bellicosus además de tres parámetros que describen su hábitat: temperatura del mar, extensión de humedales y tamaño del hábitat en cuatro zonas a lo largo de la costa de Sonora. La proporción de sexos se estimó de 25 556 jaibas muestreadas de las capturas comerciales en los años 19982002 y 2012; la temperatura media en el período de desove (mayo-agosto) se generó a partir de sensores remotos en los mismos años; la cobertura de humedales se obtuvo de reportes publicados; y el tamaño del hábitat se estimó como la superficie de pesca. Para cada zona se estimó r mediante un método desarrollado para situaciones de escasa información utilizando las capturas comerciales (t) de 1986 a 2013. Con los datos de las cuatro zonas se desarrollaron modelos de regresión lineal simple y múltiple para evaluar las sensibilidades teóricas de r a variaciones en la proporción de sexos y en los parámetros ambientales. Los machos dominaron (68.8 %) sobre las hembras en el período de estudio en las cuatro zonas; un análisis de conglomerados identificó dos grupos de acuerdo a la proporción de sexos: un grupo norteño con las zonas 1 y 2, y otro sureño con las zonas 3 y 4. Los valores de r fueron diferentes en las cuatro zonas (P<0.001) igual que la proporción de sexos (P=0.037); no se encontraron diferencias en la temperatura entre los años considerados en el estudio (P>0.995). Tanto los datos estimados como los análisis de sensibilidad sugieren que r dependen directa y positivamente de la proporción de hembras de jaiba y el tamaño de los humedales. Por lo anterior planteamos la hipótesis de que la pesca excesiva de hembras es la causa del descenso de la biomasa de jaiba café en Sonora, y concluimos que es conveniente implementar refugios pesqueros dentro de humedales costeros para proteger las hembras en el período de desove.

Abstract:The brown swimming crab (Callinectesbellicosus) is an economically important species in the Gulf of California, and its fishing activity, held in Sonora from 1986, has been affected by a 20-year declining trend in its biomass. With the aim to understand the possible reasons of this species population changes along time, we estimated population growth rate (r) and sex ratio of C. bellicosus, and combined them with three parameters describing its habitat: sea temperature, wetland extension and habitat size in four areas along the coast of Sonora. For this, monthly mean sex ratio was estimated from crabs samples obtained from commercial catches during 1998-2002 and 2012; mean sea surface temperature for the spawning period (May-August) were derived from remote sensors for the same years; while wetland coverages were obtained from published reports, and habitat size was estimated as the fishing surface. For each area, r was estimated using a method developed for limited data situations using commercial landings (t) from 1986-2013. With data from the four areas, simple and multiple linear regression models were developed to ascertain theoretical sensitivities of r to variations in sex ratio and environmental parameters. A total of 24 556 crabs were sampled; males dominated (68.8 %) over females during the study period and in all areas; a cluster analysis identified two groups according to sex ratio: a Northern group with zones 1 and 2, and a Southern group with zones 3 and 4. r values were different in all zones (P<0.001) as was sex ratio (P=0.037); no differences in temperature were identified within the study years (P>0.995). Both the estimated data and sensitivity analyses suggest the existence of a direct and positive dependence of r on the proportion of female crabs and wetland size. We hypothesize that excess fishing of females caused the declining biomass trend of the brown swimming crab in Sonora, and concluded on the convenience of implementing harvest refugia inside coastal wetlands to protect females during the spawning season. Rev. Biol. Trop. 64 (3): 1259-1271. Epub 2016 September 01.