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Resumen: Introducción: En los mamíferos, el complejo pre-Bötzinger (preBötC) es una red neuronal bilateral y simétrica localizada en el tallo cerebral, la cual es indispensable para la generación y modulación del ritmo respiratorio. En humanos existen pocos estudios acerca del preBötC y su relación con enfermedades neurológicas no ha sido descrita. Sin embargo, la importancia del preBötC en el control neural del ritmo respiratorio y su posible participación en enfermedades neurológicas en humanos ha sido mostrada gracias a la manipulación farmacológica y de lesiones del preBötC realizadas en modelos animales in vivo e in vitro. Método: En esta revisión describimos los efectos de algunos fármacos sobre la actividad inspiratoria in vitro en el modelo de rebanada transversal del tallo cerebral que contiene el preBötC, y algunos experimentos in vivo. La farmacología fue clasificada de acuerdo con los principales sistemas de neurotransmisión y con la importancia de los fármacos como estimuladores o inhibidores de la actividad del preBötC y, por tanto, de la generación del ritmo respiratorio. Conclusiones: El neurólogo clínico encontrará esta información relevante para entender cómo el sistema nervioso central genera el ritmo respiratorio y, además, podrá relacionarla con las observaciones hechas durante su práctica. Abstract: Introduction: In mammals, the preBötzinger complex (preBötC) is a bilateral and symmetrical neural network located in the brainstem which is essential for the generation and modulation of respiratory rhythm. There are few human studies about the preBötC and, its relationship with neurological diseases has not been described. However, the importance of the preBötC in neural control of breathing and its potential participation in neurological diseases in humans, has been suggested based on pharmacological manipulation and lesion of the preBötC in animal models, both in vivo and in vitro. Method: In this review, we describe the effects of some drugs on the inspiratory activity in vitro in a transverse slice that contains the preBötC, as well as some in vivo experiments. Drugs were classified according to their effects on the main neurotransmitter systems and their importance as stimulators or inhibitors of preBötC activity and therefore for the generation of the respiratory rhythm. Conclusion: Clinical neurologists will find this information relevant to understanding how the central nervous system generates the respiratory rhythm and may also relate this information to the findings made in daily practice. Palabras clave: Generación del ritmo respiratorio, Respiración, Complejo pre-Bötzinger, Control neural de la respiración, NK1R, In vitro, Keywords: Respiratory rhythm generation, Breathing, preBötzinger complex, Neural control of breathing, NK1R, In vitro

Climate change mitigation efforts require information on the current greenhouse gas atmospheric concentrations and their sources and sinks. Carbon dioxide (CO2) is the most abundant anthropogenic greenhouse gas. Its variability in the atmosphere is modulated by the synergy between weather and CO2 surface fluxes, often referred to as CO2 weather. It is interpreted with the help of global or regional numerical transport models, with horizontal resolutions ranging from a few hundreds of kilometres to a few kilometres. Changes in the model horizontal resolution affect not only atmospheric transport but also the representation of topography and surface CO2 fluxes. This paper assesses the impact of horizontal resolution on the simulated atmospheric CO2 variability with a numerical weather prediction model. The simulations are performed using the Copernicus Atmosphere Monitoring Service (CAMS) CO2 forecasting system at different resolutions from 9 to 80 km and are evaluated using in situ atmospheric surface measurements and atmospheric column-mean observations of CO2, as well as radiosonde and SYNOP observations of the winds. The results indicate that both diurnal and day-to-day variability of atmospheric CO2 are generally better represented at high resolution, as shown by a reduction in the errors in simulated wind and CO2. Mountain stations display the largest improvements at high resolution as they directly benefit from the more realistic orography. In addition, the CO2 spatial gradients are generally improved with increasing resolution for both stations near the surface and those observing the total column, as the overall inter-station error is also reduced in magnitude. However, close to emission hotspots, the high resolution can also lead to a deterioration of the simulation skill, highlighting uncertainties in the high-resolution fluxes that are more diffuse at lower resolutions. We conclude that increasing horizontal resolution matters for modelling CO2 weather because it has the potential to bring together improvements in the surface representation of both winds and CO2 fluxes, as well as an expected reduction in numerical errors of transport. Modelling applications like atmospheric inversion systems to estimate surface fluxes will only be able to benefit fully from upgrades in horizontal resolution if the topography, winds and prior flux distribution are also upgraded accordingly. It is clear from the results that an additional increase in resolution might reduce errors even further. However, the horizontal resolution sensitivity tests indicate that the change in the CO2 and wind modelling error with resolution is not linear, making it difficult to quantify the improvement beyond the tested resolutions. Finally, we show that the high-resolution simulations are useful for the assessment of the small-scale variability of CO2 which cannot be represented in coarser-resolution models. These representativeness errors need to be considered when assimilating in situ data and high-resolution satellite data such as Greenhouse gases Observing Satellite (GOSAT), Orbiting Carbon Observatory-2 (OCO-2), the Chinese Carbon Dioxide Observation Satellite Mission (TanSat) and future missions such as the Geostationary Carbon Observatory (GeoCarb) and the Sentinel satellite constellation for CO2. For these reasons, the high-resolution CO2 simulations provided by the CAMS in real time can be useful to estimate such small-scale variability in real time, as well as providing boundary conditions for regional modelling studies and supporting field experiments.

The sistematic practice physical activity in children and adolescents, improves both psychological welfare as cognitive processes and personality, both mental structures constructed during that period. Regarded as a personality trait it is identified perfectionism currently understood as a functional feature linked to positive (positive affect, self-esteem, task cohesion,...) like dysfunctional aspects have been associated with anxiety and stress. Since adolescence is a period of change and the presence of difficult situations, perceive and interpret stress in a useful way, it is an important issue for personal growth and experience psychological well-being. Therefore, the aim of this study was to identify which indicators of perfectionism provide conditions / skills for stress management in an adaptive way. Participated 127 adolescents (45 females and 82 males) aged between 13 and 17 years (M = 14.56, SD = 1.57) who completed self-reports like the Multidimensional Scale Perfectionism (FMPS), Perceived Stress Scale (PSS) and a questionnaire sociodemographic. The results indicate that the higher the frequency of AF, there are significant differences in indicators of adaptive perfectionism (personal demands and organization) and indicators of maladaptive perfectionism (parental expectations and fear of making mistakes) regarding facilitate or limit the perception of stress control. In short, research on such variables allows training and design programs for teens to know how to cope situations interpreted as stressful in an effective way. The results indicate that the higher the frequency of AF, there are significant differences in indicators of adaptive perfectionism (personal demands and organization) and indicators of maladaptive perfectionism (parental expectations and fear of making mistakes) regarding facilitate or limit the perception of stress control. In short, research on such variables allows training and design programs for teens to know how to cope situations interpreted as stressful in an effective way.

Abstract The NEXT experiment aims at searching for the hypothetical neutrinoless double-beta decay from the 136Xe isotope using a high-purity xenon TPC. Efficient discrimination of the events through pattern recognition of the topology of primary ionisation tracks is a major requirement for the experiment. However, it is limited by the diffusion of electrons. It is known that the addition of a small fraction of a molecular gas to xenon reduces electron diffusion. On the other hand, the electroluminescence (EL) yield drops and the achievable energy resolution may be compromised. We have studied the effect of adding several molecular gases to xenon (CO2, CH4 and CF4) on the EL yield and energy resolution obtained in a small prototype of driftless gas proportional scintillation counter. We have compared our results on the scintillation characteristics (EL yield and energy resolution) with a microscopic simulation, obtaining the diffusion coefficients in those conditions as well. Accordingly, electron diffusion may be reduced from about 10 mm/ m $$ \sqrt{\mathrm{m}} $$ for pure xenon down to 2.5 mm/ m $$ \sqrt{\mathrm{m}} $$ using additive concentrations of about 0.05%, 0.2% and 0.02% for CO2, CH4 and CF4, respectively. Our results show that CF4 admixtures present the highest EL yield in those conditions, but very poor energy resolution as a result of huge fluctuations observed in the EL formation. CH4 presents the best energy resolution despite the EL yield being the lowest. The results obtained with xenon admixtures are extrapolated to the operational conditions of the NEXT-100 TPC. CO2 and CH4 show potential as molecular additives in a large xenon TPC. While CO2 has some operational constraints, making it difficult to be used in a large TPC, CH4 shows the best performance and stability as molecular additive to be used in the NEXT-100 TPC, with an extrapolated energy resolution of 0.4% at 2.45 MeV for concentrations below 0.4%, which is only slightly worse than the one obtained for pure xenon. We demonstrate the possibility to have an electroluminescence TPC operating very close to the thermal diffusion limit without jeopardizing the TPC performance, if CO2 or CH4 are chosen as additives.

Alzheimer's disease (AD) is a neurodegenerative process characterized by the accumulation of extracellular deposits of amyloid β-peptide (Aβ), which induces neuronal death. Monomeric Aβ is not toxic but tends to aggregate into β-sheets that are neurotoxic. Therefore to prevent or delay AD onset and progression one of the main therapeutic approaches would be to impair Aβ assembly into oligomers and fibrils and to promote disaggregation of the preformed aggregate. Albumin is the most abundant protein in the cerebrospinal fluid and it was reported to bind Aβ impeding its aggregation. In a previous work we identified a 35-residue sequence of clusterin, a well-known protein that binds Aβ, that is highly similar to the C-terminus (CTerm) of albumin. In this work, the docking experiments show that the average binding free energy of the CTerm-Aβ1–42 simulations was significantly lower than that of the clusterin-Aβ1–42 binding, highlighting the possibility that the CTerm retains albumin's binding properties. To validate this observation, we performed in vitro structural analysis of soluble and aggregated 1 μM Aβ1–42 incubated with 5 μM CTerm, equimolar to the albumin concentration in the CSF. Reversed-phase chromatography and electron microscopy analysis demonstrated a reduction of Aβ1–42 aggregates when the CTerm was present. Furthermore, we treated a human neuroblastoma cell line with soluble and aggregated Aβ1–42 incubated with CTerm obtaining a significant protection against Aβ-induced neurotoxicity. These in silico and in vitro data suggest that the albumin CTerm is able to impair Aβ aggregation and to promote disassemble of Aβ aggregates protecting neurons. Keywords: Alzheimer's disease, Amyloid, Albumin, β-Sheet, Docking

Abstract The measurement of the internal 222Rn activity in the NEXT-White detector during the so-called Run-II period with 136Xe-depleted xenon is discussed in detail, together with its implications for double beta decay searches in NEXT. The activity is measured through the alpha production rate induced in the fiducial volume by 222Rn and its alpha-emitting progeny. The specific activity is measured to be (38.1 ± 2.2 (stat.) ± 5.9 (syst.)) mBq/m3. Radon-induced electrons have also been characterized from the decay of the 214Bi daughter ions plating out on the cathode of the time projection chamber. From our studies, we conclude that radon-induced backgrounds are sufficiently low to enable a successful NEXT-100 physics program, as the projected rate contribution should not exceed 0.1 counts/yr in the neutrinoless double beta decay sample.

Species Distribution Modelling (SDM) determines habitat suitability of a species across geographic areas using macro-climatic variables; however, micro-habitats can buffer or exacerbate the influence of macro-climatic variables, requiring links between physiology and species persistence. Experimental approaches linking species physiology to micro-climate are complex, time consuming and expensive. E.g., what combination of exposure time and temperature is important for a species thermal tolerance is difficult to judge a priori. We tackled this problem using an active learning approach that utilized machine learning methods to guide thermal tolerance experimental design for three kissing-bug species: Triatoma infestans, Rhodnius prolixus, and Panstrongylus megistus (Hemiptera: Reduviidae: Triatominae), vectors of the parasite causing Chagas disease. As with other pathogen vectors, triatomines are well known to utilize micro-habitats and the associated shift in microclimate to enhance survival. Using a limited literature-collected dataset, our approach showed that temperature followed by exposure time were the strongest predictors of mortality; species played a minor role, and life stage was the least important. Further, we identified complex but biologically plausible nonlinear interactions between temperature and exposure time in shaping mortality, together setting the potential thermal limits of triatomines. The results from this data led to the design of new experiments with laboratory results that produced novel insights of the effects of temperature and exposure for the triatomines. These results, in turn, can be used to better model micro-climatic envelope for the species. Here we demonstrate the power of an active learning approach to explore experimental space to design laboratory studies testing species thermal limits. Our analytical pipeline can be easily adapted to other systems and we provide code to allow practitioners to perform similar analyses. Not only does our approach have the potential to save time and money: it can also increase our understanding of the links between species physiology and climate, a topic of increasing ecological importance.

Despite evidence that supports cannabidiol (CBD) as an anticonvulsant agent, there remains controversy over the antiseizure efficacy, possible adverse effects, and synergistic interactions with classic antiepileptics such as valproate (VPA). The genetic audiogenic seizure hamster from the University of Salamanca (GASH/Sal) is a reliable experimental model of generalized tonic–clonic seizures in response to intense sound stimulation. The present study examines the behavioral and molecular effects of acute and chronic intraperitoneal administrations of VPA (300 mg/kg) and CBD (100 mg/kg) on the GASH/Sal audiogenic seizures, as well as the coadministration of both drugs. The GASH/Sal animals were examined prior to and after the corresponding treatment at 45 min, 7 days, and 14 days for seizure severity and neuroethology, open-field behaviors, body weight variations, and various hematological and biochemical parameters. Furthermore, the brain tissue containing the inferior colliculus (so-called epileptogenic nucleus) was processed for reverse transcription–quantitative polymerase chain reaction analysis to determine the treatment effects on the gene expression of neuronal receptors associated with drug actions and ictogenesis. Our results indicated that single dose of VPA helps prevent the animals from getting convulsions, showing complete elimination of seizures, whereas 7 days of chronic VPA treatment had few effects in seizure behaviors. Acute CBD administration showed subtle attenuation of seizure behaviors, increasing seizure latency and decreasing the duration of the convulsion phase, but without entirely seizure abolition. Chronic CBD treatments had no significant effects on sound-induced seizures, although some animals slightly improved seizure severity. Acute and chronic CBD treatments have no significant adverse effects on body weight, hematological parameters, and liver function, although locomotor activity was reduced. The combination of VPA and CBD did not alter the therapeutic outcome of the VPA monotherapy, showing no apparent synergistic effects. As compared to sham animals, chronic treatments with CBD caused abnormal mRNA expression levels for Trpv1, Adora1, Slc29a1, and Cnr1 genes, whereas no differences in gene expression were found for Htr1a and Sigmar1. Our study shed light on the behavioral and molecular effects of CBD and VPA on the GASH/Sal model and constituted the basis to develop further studies on the pharmacological effects of CBD and its interactions with other anticonvulsants.

Introduction: Being labelled as allergic to different drugs results in patients receiving other treatments, which are more toxic, less effective and more expensive. We aimed to analyze different studies of the costs of drug hypersensitivity assessment.Methods: A bibliographic search on studies regarding this issue was performed, including the available scientific evidence up to June 2020. We searched three databases with terms related to costs and allergy testing in drug hypersensitivity reactions.Results: Our search revealed 1,430 publications, of which 20 met the inclusion criteria. In the manuscript, prospective studies evaluating the costs of the evaluation of patients with suspected allergy to beta-lactams or non-steroidal anti-inflammatory drugs are analyzed. Also, comment is made on the costs associated with incorrect labeling as non-steroidal anti-inflammatory drug or penicillin hypersensitivity.Conclusions: Taking all costs into account, the study of drug hypersensitivity is not expensive, particularly considering the economic and clinical consequences of labeling a patient with hypersensitivity to drugs.

El objetivo del trabajo fue realizar una revisión de la literatura relacionada con la actividad física como medio de inclusión para personas con Síndrome de Down. Para la búsqueda de referencias, se utilizó las siguientes palabras clave: Inclusion, Down Syndrome, y Physical Activity. Las bases de datos utilizadas fueron Web Of Science y SCOPUS. Para limitar la búsqueda, se establecieron cinco criterios de inclusión: i) Mencionar al menos alguna de las características de las personas con Síndrome de Down, ii) Utilizar la Actividad Física como herramienta de mejora de la calidad de vida iii) Seleccionar solamente artículos científicos, iiii) Disponibilidad del texto completo, y iiiii) Estar escrito en lengua inglesa. Se seleccionaron veintiún estudios, donde se extrajeron los datos de los artículos incluidos en la revisión. Los documentos abordan tópicos de investigación diferentes y han permitido conocer los principales beneficios de la actividad física para mejorar la calidad de vida de las personas con Síndrome de Down.

The current COVID-19 crisis has exposed new and existing issues related to access and equity for our students and families. The following article discusses a model for interconnecting educators, families, and community health workers (CHW) that can integrate diversity and equity for practitioners and educator preparation programs. Integrating CHWs provides a unique opportunity to utilize their cultural responsive skills and knowledge. Implications for practitioners and educator preparation programs are discussed.

Many epithelial developmental processes like cell migration and spreading, cell sorting, or T1 transitions can be described as planar deformations. As such, they can be studied using two-dimensional tools and vertex models that can properly predict collective dynamics. However, many other epithelial shape changes are characterized by out-of-plane mechanics and three-dimensional effects, such as bending, cell extrusion, delamination, or invagination. Furthermore, during planar cell dynamics or tissue repair in monolayers, spatial intercalation between the apical and basal sides has even been detected. Motivated by this lack of symmetry with respect to the midsurface, we here present a 3D hybrid model that allows us to model differential contractility at the apical, basal or lateral sides. We use the model to study the effects on wound closure of solely apical or lateral contractile contributions and show that an apical purse-string can be sufficient for full closure when it is accompanied by volume preservation.

Abstract Splicing, the process that catalyzes intron removal and flanking exon ligation, can occur in different ways (alternative splicing) in immature RNAs transcribed from a single gene. In order to adapt to a particular context, cells modulate not only the quantity but also the quality (alternative isoforms) of their transcriptome. Since 95% of the human coding genome is subjected to alternative splicing regulation, it is expected that many cellular pathways are modulated by alternative splicing, as is the case for the DNA damage response. Moreover, recent evidence demonstrates that upon a genotoxic insult, classical DNA damage response kinases such as ATM, ATR and DNA-PK orchestrate the gene expression response therefore modulating alternative splicing which, in a reciprocal way, shapes the response to a damaging agent.

[This corrects the article DOI: 10.1371/journal.pone.0229953.].

Epilepsy is a complex neurological disorder characterized by sudden and recurrent seizures, which are caused by various factors, including genetic abnormalities. Several animal models of epilepsy mimic the different symptoms of this disorder. In particular, the genetic audiogenic seizure hamster from Salamanca (GASH/Sal) animals exhibit sound-induced seizures similar to the generalized tonic seizures observed in epileptic patients. However, the genetic alterations underlying the audiogenic seizure susceptibility of the GASH/Sal model remain unknown. In addition, gene variations in the GASH/Sal might have a close resemblance with those described in humans with epilepsy, which is a prerequisite for any new preclinical studies that target genetic abnormalities. Here, we performed whole exome sequencing (WES) in GASH/Sal animals and their corresponding controls to identify and characterize the mutational landscape of the GASH/Sal strain. After filtering the results, moderate- and high-impact variants were validated by Sanger sequencing, assessing the possible impact of the mutations by "in silico" reconstruction of the encoded proteins and analyzing their corresponding biological pathways. Lastly, we quantified gene expression levels by RT-qPCR. In the GASH/Sal model, WES showed the presence of 342 variations, in which 21 were classified as high-impact mutations. After a full bioinformatics analysis to highlight the high quality and reliable variants, the presence of 3 high-impact and 15 moderate-impact variants were identified. Gene expression analysis of the high-impact variants of Asb14 (ankyrin repeat and SOCS Box Containing 14), Msh3 (MutS Homolog 3) and Arhgef38 (Rho Guanine Nucleotide Exchange Factor 38) genes showed a higher expression in the GASH/Sal than in control hamsters. In silico analysis of the functional consequences indicated that those mutations in the three encoded proteins would have severe functional alterations. By functional analysis of the variants, we detected 44 significantly enriched pathways, including the glutamatergic synapse pathway. The data show three high-impact mutations with a major impact on the function of the proteins encoded by these genes, although no mutation in these three genes has been associated with some type of epilepsy until now. Furthermore, GASH/Sal animals also showed gene variants associated with different types of epilepsy that has been extensively documented, as well as mutations in other genes that encode proteins with functions related to neuronal excitability, which could be implied in the phenotype of the GASH/Sal. Our findings provide valuable genetic and biological pathway data associated to the genetic burden of the audiogenic seizure susceptibility and reinforce the need to validate the role of each key mutation in the phenotype of the GASH/Sal model.

Purpose. To assess the efficacy, safety, and predictability of the Visian Implantable Collamer Lens (ICL) model having a central port in patients over 40 years of age. Methods. This study included 33 eyes from 21 patients who underwent V4c ICL implantation for the correction of myopia and myopic astigmatism. We assessed uncorrected (UDVA) and corrected (CDVA) distance visual acuity, refraction, intraocular pressure (IOP), endothelial cell density (ECD), vault, and adverse events occurring over a 1-year period. Results. Mean age of the patients at the time of implantation was 43.52 ± 4.49 years (range: 40 to 56 years). Efficacy and safety indexes were 1 and 1.09, respectively. Surgical outcomes for CDVA were as follows: no eye lost any lines, 19 eyes (57.58%) showed no CDVA changes, 7 eyes (21.21%) gained 1 line, 4 eyes (12.12%) gained 2 lines, and 3 eyes (9.09%) gained ≥3 lines. Mean postoperative spherical equivalent (SE) was −0.09 ± 0.47 D. A total of 29 eyes (87.8%) were within ±0.50 D and 31 eyes (93.9%) were within ±1.00 D of the desired SE. At 1-year, mean IOP was 15.27 ± 3.03 mmHg (range: 9 to 20 mmHg, p=0.12 pre vs. post) and mean ECD was 2516 ± 234 cells/mm2 (p=0.29 pre vs. post). Mean postoperative vault was 320 ± 136 μm, with 201–300 μm being the most prevalent vault range for 9 eyes (31.03%). None of the eyes showed a vault >701 μm. There were neither intraoperative nor postoperative complications; in fact, all ICL implantation procedures were uneventful. Conclusions. Our study’s findings support the use of this lens in patients over 40 years of age. A long follow-up period is advisable to monitor ICL position relative to the crystalline lens.

La base de datos de la Red Hidrométrica de la Armada Boliviana (RHAB) carecía de la agilidad de consulta, por lo que precisa de un moderno gestor de información espacial y de base de datos para la optimización del manejo de los recursos hidrológicos. Por ello, se presenta una nueva metodología, generalizable a cualquier país, para desarrollar un sistema multidisciplinario de información geográfico (SIG) en Internet. Es de fácil e intuitiva utilización, orientado a la gestión de información hidrométrica para alerta temprana, apoyo a la navegación, al transporte fluvial y lacustre, para proyectos y obras de investigación, ingeniería, cartografía, pesca y turismo, entre otros. El acceso a la base de datos geográfica que contiene la información hidrológica se realiza mediante Internet, con un visor web geográfico. Se han integrado diferentes aplicaciones de software de distribución libre, junto con diversos lenguajes de programación. La disposición inmediata de datos precisos coadyuva en la prevención de desastres por inundaciones.

Aim of the study: Postoperative intra-abdominal abscess (PIAA) is a frequent and severe complication of acute appendicitis (AA) with peritonitis. The neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker that has been related to the development of peritonitis; however, its diagnostic role in predicting PIAA has not been evaluated. This is the first study that analyzes the usefulness of NLR as a predictor of PIAA in children operated for AA.Material and Methods: Retrospective observational study in children operated for AA in our institution during 2017–2018. Patients aged under 5 years or with incomplete laboratory determinations at hospital admission (blood count, C-reactive protein, and fibrinogen) were excluded. Demographic and laboratory parameters and the development of PIAA were analyzed. NLR was calculated by dividing the absolute number of neutrophils by the absolute number of lymphocytes. By means of ROC curves, we determined the sensitivity and specificity of the different laboratory parameters to predict the development of PIAA.Results: A total of 388 patients aged 10.5 ± 2.9 year were included. Twenty (5.2%) developed PIAA. NLR presented an area under the curve (AUC) of 0.85, significantly higher than the determination of leukocytes (AUC 0.69, p < 0.001), neutrophils (AUC 0.74, p < 0.001), fibrinogen (AUC 0.68, p < 0.001) and C-reactive protein (AUC 0.73, p < 0.001). We estimated the optimal cut-off point of NLR > 10.5, with a sensitivity of 85% and a specificity of 75.2%.Conclusions: NLR is the laboratory parameter with the highest sensitivity and specificity for predicting the development of PIAA in children operated for AA. It can be useful as a predictor of worse postoperative course.

Abstract Background Advances in automated image-based microscopy platforms coupled with high-throughput liquid workflows have facilitated the design of large-scale screens utilising multicellular model organisms such as Caenorhabditis elegans to identify genetic interactions, therapeutic drugs or disease modifiers. However, the analysis of essential genes has lagged behind because lethal or sterile mutations pose a bottleneck for high-throughput approaches, and a systematic way to analyse genetic interactions of essential genes in multicellular organisms has been lacking. Results In C. elegans, non-conditional lethal mutations can be maintained in heterozygosity using chromosome balancers, commonly expressing green fluorescent protein (GFP) in the pharynx. However, gene expression or function is typically monitored by the use of fluorescent reporters marked with the same fluorophore, presenting a challenge to sort worm populations of interest, particularly at early larval stages. Here, we develop a sorting strategy capable of selecting homozygous mutants carrying a GFP stress reporter from GFP-balanced animals at the second larval stage. Because sorting is not completely error-free, we develop an automated high-throughput image analysis protocol that identifies and discards animals carrying the chromosome balancer. We demonstrate the experimental usefulness of combining sorting of homozygous lethal mutants and automated image analysis in a functional genomic RNA interference (RNAi) screen for genes that genetically interact with mitochondrial prohibitin (PHB). Lack of PHB results in embryonic lethality, while homozygous PHB deletion mutants develop into sterile adults due to maternal contribution and strongly induce the mitochondrial unfolded protein response (UPRmt). In a chromosome-wide RNAi screen for C. elegans genes having human orthologues, we uncover both known and new PHB genetic interactors affecting the UPRmt and growth. Conclusions The method presented here allows the study of balanced lethal mutations in a high-throughput manner. It can be easily adapted depending on the user’s requirements and should serve as a useful resource for the C. elegans community for probing new biological aspects of essential nematode genes as well as the generation of more comprehensive genetic networks.

European traditional cultural landscapes are increasingly modified by rural abandonment and urban growth processes. Acknowledged as of High Nature Value for providing multiple ecosystem services while contributing to human well-being, the future of these social-ecological systems is uncertain. Here we aim to (1) explore dominant land use and cover (LULC) changes linked to extensive livestock farming across an urban-rural gradient defined by a large city (Madrid) over the last three decades; (2) identify and classify the main driving forces shaping these landscape trajectories and; (3) acknowledge the main landscape values for promoting landscape stewardship under participatory governance frameworks. For doing so, we combine mapping analyses (CORINE Land cover) with stakeholder perceptions and positions. Our results show a dual process of progressive abandonment of agroecosystems linked to traditional livestock farming and an ever-increasing urban growth over the last three decades as the most important driving forces. The growing urban sprawl in areas close to Madrid begins to be perceived as problematic for interviewees. The decline of extensive livestock farming in detriment of tourism, particularly evident in rural areas far from Madrid, is perceived as a threat to the cultural heritage and traditions of rural people. This decline is also perceived as a worrying increase of wildfire risk. Stakeholders stressed the need of valuing extensive livestock farming to prevent rural-urban migration, dynamizing rural economies, conserving landscapes and traditions while producing food-quality products. Interviewees advocated for science-based, stakeholder-inclusive and participatory landscape planning and co-management, leading to more context-specific, regionalized policymaking.

In recent years changes in higher education, as a result of convergence to European Higher Education Area, are pointing towards a more active learning by the students and also towards a teachers’ new role. This new role involves providing to the students the conditions for learning and accompanying them through the learning process. This paper presents the adaptation process since 2003 to the new context in a basic Subject of the Veterinary Degree: Pharmacology. During this period, problem-based learning and Aronson’s jigsaw have been introduced to acquire specific competencies in Therapeutics and in Pharmaceutical Forms respectively, furthermore of other transversal competencies offered by these methodologies. Students’ self-assessment and teamwork students’ peer assessment have been also included. Moreover other experiences have been developed, including coordination with another subject, General Pathology, to solve common problems and clinical cases, and to prepare materials about pharmacological research in infectious and parasitic processes. In general, these new experiences have been highly valuated by all stakeholders: students and faculty.