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The risk posed globally by surface water flooding to people and properties is growing due to rapid urbanisation and the intensification of rainfall due to climate change. Whilst tools to model urban flood risk have also been rapidly developing, there remains a knowledge gap around the sensitivity of urban hydraulic modelling methods to the temporal structure of rainfall. In the UK, the industry standard process considers rainfall events to always be symmetrical, and with a singular peak in intensity. Previous studies of observed UK extreme rainfall events suggests that loading of rainfall towards the start or end of events is in fact more common. In this study, the sensitivity of an urban catchment in the north of England is tested using fifteen realistic rainfall profiles derived from these observed extremes. Additionally, idealized systematic variations are made to the industry standard profile to shift the single peak towards the start or end of the event, and to split the rainfall volume over multiple peaks. We demonstrate that the positioning of the peak, as well as its magnitude, influences the severity, timing and nature of the associated flooding. The profile with the peak nearest the end of the event is associated with an 18% larger flooded area than the early peaking profile which is associated with the smallest flooded area.

Background Baricitinib is a treatment authorized by the FDA for the treatment of moderate to severe COVID-19, despite this there are few approved drugs; polymerized type I collagen (PTIC) is a drug that has been used in Mexico with great potential for treating moderate to severe cases of COVID-19. Methods Comparative, descriptive and retrospective analysis of two populations of adult patients affected by COVID-19 confirmed by antigen test or RT-PCR as well as CO-RADS 6 CT, who consented to be treated between 2020 and 2021, a population using oral baricitinib at a dose of 4mg/day/14 days and another using polymerized type I collagen intramuscularly at a dose of 1.5ml every 12 hours for 3 days, followed by 1.5ml every 24 hours for 4 days; The most affected age and gender, comorbidities and laboratory abnormalities are analyzed, as well as improvement in inflammatory and oxygenation indices measured by pulse oximetry and SAFI (SpO2/FiO2), finally the outcome of the patients and the presence of adverse events. Results 80 patients for each group, the most affected gender was male; the average age in the PTIC group was 51 years and in the baricitinib group it was 56 years; the main comorbidities were obesity, diabetes and hypertension in both groups; the decrease in acute phase reactants such as CRP, D-dimer and ferritin was greater in the PTIC group compared to the baricitinib group, the latter drug requiring a regimen of more days to achieve the objectives of the first drug (PTIC 7 days and baricitinib 14 days); Similarly, in oxygenation measured, the PTIC group reached goals in less time compared to the baricitinib group, which required twice as many days of treatment to achieve adequate oxygenation; Regarding the outcomes, there was a higher mortality in the baricitinib group compared to the PTIC group (6.25% vs 3.75%). Regarding adverse events reported for the PTIC group, they were minor and related to the intramuscular administration of the drug in 7 patients, while in the baricitinib group, 5 patients were reported with added bacterial pneumonia. Conclusion Polymerized type I collagen has anti-inflammatory and immunomodulatory potential similar to baricitinib in cases of moderate to severe COVID-19, even reaching treatment goals in less time both in inflammatory indices and in oxygenation indices. Disclosures All Authors: No reported disclosures.

Background Since the beginning of the pandemic and its passage through the different affected continents, there have been differences in the presentation depending in part on the characteristics of each population, so it is important to know how it behaves in the local population. Methods Clinical-epidemiological study in adults hospitalized for suspected COVID-19 at the General Hospital 71 of the City of Veracruz, Mexico, from April to December 2020. Demographic and clinical characteristics are studied, as well as a comparative and stratified analysis was performed by intubation and death. Results 1212 patients are included, 53% are men, average age 49 years. 20.5% reported sudden onset of symptoms; the most frequent: fever (79.8%), headache (75.2%), cough (71%), myalgia (62%), arthralgia (58%) and dyspnea (46.3%). Comorbidities were reported in 54.7%, the most frequent: Hypertension (29.2%), Diabetes (29.1%) and obesity (13.9%). Regarding the outcomes, 120 (9.9%) required intubation and 300 (25%) died. Men requiring intubation were significantly older than women [62.5 vs 37.5%; p = 0.027]. The mean age of the intubated patients was higher compared to that of the non-intubated [60.5 vs 44.8 years; p = 0.001]. The male gender had a risk association for intubation. The group aged 60 years or older compared to those aged 59 years or younger had a higher risk of intubation. Clinical variables that had a risk association with intubation were: dyspnea, chest pain and prostration. Among comorbidities, hypertension and diabetes had a risk association with intubation. Female gender and headache had a protective association for intubation. In addition, odynophagia, rhinorrhea, and abdominal pain showed a protective association for intubation. There was no difference in terms of gender by death. The mean age of the patients who died was significantly older [64.5 vs 43.8 years; p = 0.001]. The clinical variables that had a risk association with death were: dyspnea, chest pain, polypnea, cyanosis and prostration. The protective variables were: rhinorrhea, odynophagia, headache and conjunctivitis. Conclusion By studying a population affected by COVID, its own characteristics and inherent risks can be known to help take local diagnosis and treatment strategies that ensure a better outcome for those affected. Disclosures All Authors: No reported disclosures.

Preeclampsia (PE) is a pregnancy syndrome characterized by new-onset hypertension and end-organ dysfunction. The pathophysiology of PE remains undetermined, but it is thought that maternal vascular dysfunction plays a central role, potentially due, in part, to the release of syncytiotrophoblast-derived extracellular vesicles (STBEVs) into the maternal circulation by a dysfunctional placenta. STBEVs from normal pregnancies (NP) impair vascular function, but the effect of PE STBEVs (known to differ in composition with elevated circulating levels) on vascular function are not known. We hypothesized that PE STBEVs have more detrimental effects on vascular function compared with NP STBEVs. STBEVs were collected by perfusion of placentas from women with NP or PE. Mesenteric arteries from pregnant rats were incubated overnight with NP or PE STBEVs, and vascular function was assessed by wire myography. NP and PE STBEVs impaired endothelial function, partially by reducing nitric oxide (NO) bioavailability. Incubation of human umbilical vein endothelial cells with NP and PE STBEVs increased nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) activation, reactive oxygen species, nitrotyrosine levels, and reduced NO levels. However, PE STBEVs increased NF-κB activation and nitrotyrosine levels to a lesser extent than NP STBEVs. Taken together, no greater impact of PE STBEVs compared with NP STBEVs on endothelial function was found. However, the impaired vascular function by PE STBEVs and increased levels of STBEVs in PE suggest PE STBEVs may contribute to maternal vascular dysfunction in PE. Our study further expands on the potential mechanisms that lead to adverse outcomes in PE and provides potential targets for future interventions.

Gestational hypoxia is a major contributor to fetal growth restriction (FGR) and perinatal morbidity and mortality and has been closely linked to the activation of the unfolded protein response (UPR) in the placenta. Recent studies on adverse pregnancy conditions show differential adaptive responses in pregnancies carrying male or female fetuses. Here, we use an established rat model of hypoxic pregnancy and FGR to test the hypothesis that chronic hypoxia promotes sexually dimorphic activation of the placental UPR. Our data showed that gestational hypoxia increased glucose regulatory protein 78 (GRP78) expression in male placentae, increased activating transcription factor 6 activation (ATF6) in female placentae, and did not induce changes in other UPR markers. In addition, gestational hypoxia reduced fetal weight only in males and ATF6 activation correlated with an increase in the fetal crown-rump-length/body weight ratio only in females. These results suggest sex-specific divergence in the placental adaptive response to gestational hypoxia, which may account for the sexual dimorphism observed in placental function and pregnancy outcomes in complicated pregnancies. Graphical Abstract

We investigate the global distribution of hourly precipitation and its connections with the El Niño–Southern Oscillation (ENSO) using both satellite precipitation estimates and the global sub-daily rainfall gauge dataset. Despite limited moisture availability over continental surfaces, we find that the highest mean and extreme hourly precipitation intensity (HPI) values are mainly located over continents rather than over oceans, a feature that is not evident in daily or coarser resolution data. After decomposing the total precipitation into the product of the number of wet hours (NWH) and HPI, we find that ENSO modulates total precipitation mainly through the NWH, while its effects on HPI are more limited. The contrasting responses to ENSO in NWH and HPI is particularly apparent at the rising branches of the Pacific and Atlantic Walker Circulations, and is also notable over land-based gauges in Australia, Malaysia, the USA, Japan and Europe across the whole distribution of hourly precipitation (i.e. extreme, moderate and light precipitation). These results provide new insights into the global precipitation distribution and its response to ENSO forcing.

Everything seemed to go well in the winter of 2019 in Mexico City, but it was exactly a year ago, on February of 2020 when television networks, news outlets and social networks informed that the first case of SARS-CoV-2 had been detected in Mexico. Until that moment, the student community belonging to higher education, which I was a part of, had seen a similar case 11 years before, in 2009, with the A H1N1 influenza, without evident consequences. With the help of digital technology, we got news from all over the world regarding the expansion of COVID-19. We would read about politicians establishing drastic and unimaginable preventive measures such as the closure of borders and airports, the use of face masks, eyewear, gloves, etc. Likewise, a ‘war’ broke out between the main global powers over security inputs and to find who was guilty and/or responsible for this virus. The blame was placed on the vendors and consumers of the market in the city of Wuhan in China, due to a bat soup or eating pangolin. Mexicans are characteristically known for our dark humor and the way in which we laugh at hardships. The jokes with COVID-19 were inevitable. But we had no idea what lay ahead for us. Wednesday, March 18, 2020, was the last day I entered the Universidad Autónoma Metropolitana-Xochimilco (UAM-X) in a normal way. That day, we only went to find out which our grades were going to be for the eleventh, penultimate, term of my degree. When we left my professor’s office, delighted with my grades, three friends and I decided to celebrate with beers and finger foods in the Xochimilco wharf, near the university. That was the day I later called ‘the silent goodbye to our dreams’. But meanwhile, we enjoyed being only three months away from …graduating! Some were doing their undergraduate social service and others would begin soon. We would comment and laugh. ‘Yeah, my friend. In a year we’ll be here as engineers, working on whatever we want, on something we like, holding the name of UAM-X high’. We would chat about our experiences and thank our beautiful ‘House open to time’. Words thrown to the wind with a touch of happiness and hope, perhaps with much innocence, since we had no idea of the labor market in a country like ours. Dreams, beautiful dreams that drowned as months went by. At exactly 17:00 h, we said goodbye, and our last words were, ‘see you in two weeks’. Two days later, the Mexican government announces that all non-essential activity, including educational activities, was suspended until April 20, and social distancing and voluntary home confinement were in place. The development of the pandemic in Mexico forced the government to extend preventive COVID-19 measures. We started to realize what was going on. There was still much confusion. We knew everything was lost when they told us that the lessons for the twelfth and thirteenth terms would be online, via Zoom or Google Classroom. Goodbye graduation, goodbye to the last get-togethers with classmates, goodbye professors, goodbye to my beloved alma mater. Time kept ticking, never stopping. What did come to a stop were the hopes of all my classmates, friends, my own, our ambitions of working on the fields of Mexico as freshly graduated agronomists. Practicing the theory and ethics that our professors and our university had taught us for four years. Serving our country, our society, finding solutions to problems on the field; social problems, economic problems, from the different areas in which an agronomist and anyone who graduated from UAM-X is trained to cope... All that was left were ‘lost dreams, lost dreams of someone recently graduated, thanks to the pandemic’. Mental problems and anxieties trouble us. Digital technology has stopped being a hobby to be used for its intended purpose, a beneficial everyday tool for human beings. I mention this because thanks to digital media, I have kept in touch with my friends and professors and I have taken some agronomy courses I was interested in. We all complain about this pandemic, we all say it truncated our path and we all have anxieties for having to stay at home. Our everyday lives have changed; some people don’t accept this and have suffered the consequences of it. Some people go about their lives, regardless of what may happen. Different thoughts, but with a common and inevitable reality that I can summarize in three words: ‘fear of death’. As a final thought on what has occurred in these long months of the pandemic, I can express that, as young adults we must let go of consumerism and learn to manage our time and money. To be determined and focus on what we want and need, regardless of outside opinions, yet accept our abilities and limitations to make assertive decisions. To acknowledge and defend our convictions in politics, religion and social networks regarding how we dress, our sexuality, music, and sports such as soccer. Acknowledge their vlues in our daily lives. Not wanting to emulate tendencies or people of a higher social class; accepting the reality we live in, identifying the way things are. The way we are. To value and respect everyone who is a part of our lives. We must work to obtain what we want and end absurd stereotypes. To awaken that nationalistic spirit that we have fallen behind with as Mexicans, to feel proud of belonging to this country and give back to Mexico all it has given us by working hard and lending a hand in society. From here, I thank my parents for supporting me all through my life, regardless of what I did or how. I thank and hold deep love for the Universidad Autónoma Metropolitana Unidad Xochimilco for having given me the pleasure of its student community. I thank my professors that supported me from May 9, 2016 until today. Some I agreed with in thought and with others, not so much, but I learned lots from them all. I hope others identify with these words I spilled with honesty onto these pages. I am eager for this pandemic to be controlled soon; that there are no more human losses, that the Mexican agriculture goes back to normal and that the economy also slowly recovers. But especially, that the thousands of newly graduated agronomists, those of us who live with frustrated dreams...losted, can work in educational, professional and scientific fields.

Pregnant women that are obese may develop gestational diabetes mellitus (GDM) configuring a new metabolic condition referred to as gestational diabesity. The metabolic alterations seen in gestational diabesity include a combination of an exacerbated pro-inflammatory state and fetoplacental endothelial dysfunction. Also, gestational diabesity associates with supra-physiological extracellular concentration of adenosine in the foetoplacental blood. Since adenosine plays a central role in the inflammatory response in GDM and obesity, it is likely that this nucleoside will play a similar role in gestational diabesity. However, the effect of adenosine in the foetoplacental vasculature in this condition is not yet addressed. Adenosine exerts its biological actions via four adenosine receptors. Activation of A2B adenosine receptors (A2BAR) subtype associates with an anti-inflammatory response in several tissue and diseases. In tissues from pregnant women with GDM, there is an overexpression of A2BAR, and higher mRNA expression of ADORA2B (for A2BAR) was shown to correlate with hyperglycaemia and oxidative stress. A2BAR shows low affinity for adenosine (micromolar) and its activation results in triggering intracellular signalling cascades lowering the inflammatory response. This phenomenon requires a high level of extracellular adenosine in diseases of pregnancy such as GDM or gestational diabesity. In this review, we focused on the role of A2BAR involvement in the biological actions of adenosine on inflammation in the foetoplacental vasculature in gestational diabesity. Some factors including oxidative stress and hypoxia in this phenomenon are discussed.

Diabesity is an abnormal metabolic condition shown by patients with obesity that develop type 2 diabetes mellitus. Patients with diabesity present with insulin resistance, reduced vascular response to insulin, and vascular endothelial dysfunction. Along with the several well-described mechanisms of insulin resistance, a state of endoplasmic reticulum (ER) stress, where the primary human targets are the adipose tissue, liver, skeletal muscle, and the foetoplacental vasculature, is apparent. ER stress characterises by the activation of the unfolded protein response via three canonical ER stress sensors, i.e., the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6. Slightly different cell signalling mechanisms preferentially enable in diabesity in the ER stress-associated insulin resistance for adipose tissue (IRE1α/X-box binding protein 1 mRNA splicing/c-jun N-terminal kinase 1 activation), skeletal muscle (tribbles-like protein 3 (TRB3)/proinflammatory cytokines activation), and liver (PERK/activating transcription factor 4/TRB3 activation). There is no information in human subjects with diabesity in the foetoplacental vasculature. However, the available literature shows that pregnant women with pre-pregnancy obesity or overweight that develop gestational diabetes mellitus (GDM) and their newborn show insulin resistance. ER stress is recently reported to be triggered in endothelial cells from the human umbilical vein from mothers with pre-pregnancy obesity. However, whether a different metabolic alteration to obesity in pregnancy or GDM is present in women with pre-pregnancy obesity that develop GDM, is unknown. In this review, we summarised the findings on diabesity-associated mechanisms of insulin resistance with emphasis in the primary targets adipose, skeletal muscle, liver, and foetoplacental tissues. We also give evidence on the possibility of a new GDM-associated metabolic condition triggered in pregnancy by maternal obesity, i.e. gestational diabesity, leading to ER stress-associated insulin resistance in the human foetoplacental vasculature.

A large number of recent studies have aimed at understanding short-duration rainfall extremes, due to their impacts on flash floods, landslides and debris flows and potential for these to worsen with global warming. This has been led in a concerted international effort by the INTENSE Crosscutting Project of the GEWEX (Global Energy and Water Exchanges) Hydroclimatology Panel. Here, we summarize the main findings so far and suggest future directions for research, including: the benefits of convection-permitting climate modelling; towards understanding mechanisms of change; the usefulness of temperature-scaling relations; towards detecting and attributing extreme rainfall change; and the need for international coordination and collaboration. Evidence suggests that the intensity of long-duration (1 day+) heavy precipitation increases with climate warming close to the Clausius–Clapeyron (CC) rate (6–7% K −1 ), although large-scale circulation changes affect this response regionally. However, rare events can scale at higher rates, and localized heavy short-duration (hourly and sub-hourly) intensities can respond more strongly (e.g. 2 × CC instead of CC). Day-to-day scaling of short-duration intensities supports a higher scaling, with mechanisms proposed for this related to local-scale dynamics of convective storms, but its relevance to climate change is not clear. Uncertainty in changes to precipitation extremes remains and is influenced by many factors, including large-scale circulation, convective storm dynamics andstratification. Despite this, recent research has increased confidence in both the detectability and understanding of changes in various aspects of intense short-duration rainfall. To make further progress, the international coordination of datasets, model experiments and evaluations will be required, with consistent and standardized comparison methods and metrics, and recommendations are made for these frameworks. This article is part of a discussion meeting issue ‘Intensification of short-duration rainfall extremes and implications for flash flood risks’.

Research into potential implications of climate change on flood hazard has made significant progress over the past decade, yet efforts to translate this research into practical guidance for flood estimation remain in their infancy. In this commentary, we address the question: how best can practical flood guidance be modified to incorporate the additional uncertainty due to climate change? We begin by summarizing the physical causes of changes in flooding and then discuss common methods of design flood estimation in the context of uncertainty. We find that although climate science operates across aleatory, epistemic and deep uncertainty, engineering practitioners generally only address aleatory uncertainty associated with natural variability through standards-based approaches. A review of existing literature and flood guidance reveals that although research efforts in hydrology do not always reflect the methods used in flood estimation, significant progress has been made with many jurisdictions around the world now incorporating climate change in their flood guidance. We conclude that the deep uncertainty that climate change brings signals a need to shift towards more flexible design and planning approaches, and future research effort should focus on providing information that supports the range of flood estimation methods used in practice. This article is part of a discussion meeting issue ‘Intensification of short-duration rainfall extremes and implications for flash flood risks'.

This report looks at the policies and programmes Chile has been putting in place over the past few decades to foster the development of public transport in remote communities. In particular, it has been taking a regional approach and encouraging private investment in transport.

Climate models' outputs are affected by biases that need to be detected and adjusted to model climate impacts. Many climate hazards and climate-related impacts are associated with the interaction between multiple drivers, i.e. by compound events. So far climate model biases are typically assessed based on the hazard of interest, and it is unclear how much a potential bias in the dependence of the hazard drivers contributes to the overall bias and how the biases in the drivers interact. Here, based on copula theory, we develop a multivariate bias-assessment framework, which allows for disentangling the biases in hazard indicators in terms of the underlying univariate drivers and their statistical dependence. Based on this framework, we dissect biases in fire and heat stress hazards in a suite of global climate models by considering two simplified hazard indicators: the wet-bulb globe temperature (WBGT) and the Chandler burning index (CBI). Both indices solely rely on temperature and relative humidity. The spatial pattern of the hazard indicators is well represented by climate models. However, substantial biases exist in the representation of extreme conditions, especially in the CBI (spatial average of absolute bias: 21 ∘C) due to the biases driven by relative humidity (20 ∘C). Biases in WBGT (1.1 ∘C) are small compared to the biases driven by temperature (1.9 ∘C) and relative humidity (1.4 ∘C), as the two biases compensate for each other. In many regions, also biases related to the statistical dependence (0.85 ∘C) are important for WBGT, which indicates that well-designed physically based multivariate bias adjustment procedures should be considered for hazards and impacts that depend on multiple drivers. The proposed compound-event-oriented evaluation of climate model biases is easily applicable to other hazard types. Furthermore, it can contribute to improved present and future risk assessments through increasing our understanding of the biases' sources in the simulation of climate impacts.

Gestational diabetes mellitus (GDM) is a disease of pregnancy that is associated with d-glucose intolerance and foeto-placental vascular dysfunction. GMD causes mitochondrial dysfunction in the placental endothelium and trophoblast. Additionally, GDM is associated with reduced placental oxidative phosphorylation due to diminished activity of the mitochondrial F0F1-ATP synthase (complex V). This phenomenon may result from a higher generation of reactive superoxide anion and nitric oxide. Placental mitochondrial biogenesis and mitophagy work in concert to maintain cell homeostasis and are vital mechanisms securing the efficient generation of ATP, whose demand is higher in pregnancy, ensuring foetal growth and development. Additional factors disturbing placental ATP synthase activity in GDM include pre-gestational maternal obesity or overweight, intracellular pH, miRNAs, fatty acid oxidation, and foetal (and 'placental') sex. GDM is also associated with maternal and foetal hyperinsulinaemia, altered circulating levels of adiponectin and leptin, and the accumulation of extracellular adenosine. Here, we reviewed the potential interplay between these molecules or metabolic conditions on the mechanisms of mitochondrial dysfunction in the foeto-placental unit in GDM pregnancies.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by severe and persistent fatigue. Along with clinical studies showing endothelial dysfunction (ED) in a subset of ME/CFS patients, we have recently reported altered ED-related microRNAs in plasma from affected individuals. Inadequate nitric oxide (NO), mainly produced by the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells (ECs), is a major cause of ED. In this study, we hypothesized that plasma from that cohort of ME/CFS patients induces eNOS-related ED in vitro. To test this, we cultured human umbilical vein endothelial cells (HUVECs) in the presence of plasma from either ME/CFS patients (ME/CFS-plasma, n = 11) or healthy controls (HC-plasma, n = 12). Then, we measured the NO production in the absence and presence of tyrosine kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively), well-known to activate eNOS in ECs. Our data showed that HUVECs incubated with ME/CFS-plasma produced less NO either in the absence or presence of eNOS activators compared to ones in presence of HC-plasma. Also, the NO production elicited by bradykinin, histamine, and acetylcholine (GPCRs agonists) was more affected than the one triggered by insulin (TKR agonist). Finally, inhibitory eNOS phosphorylation at Thr

Desde sus orígenes, el hombre ha sentido la necesidad de enseñar y transmitir sus conocimientos, experiencias y descubrimientos a las generaciones siguientes. Por esta razón, podemos considerar que la enseñanza como actividad humana ha ido dándose de una u otra manera con los recursos propios de cada sociedad, en su momento, manejándose con frecuencia a base de verdades acabadas o estáticas.

Introducción: En Costa Rica el paraquat es el tercer plaguicida más importado debido a que se aplica ampliamente en diferentes plantaciones. Esto hace que sea necesario tener un estricto control de calidad del producto para asegurar que cumple con el Decreto Ejecutivo Nº 34139-S-MAG-TSS-MINAE, el cual regula el registro, la fabricación, la formulación, el reempaque, el almacenamiento, la venta, la mezcla, la comercialización y uso, de materia prima o producto formulado, de los productos que contengan el plaguicida agrícola dicloruro de paraquat (Montero, 2018). Objetivo: Verificar y comparar los métodos normalizados 969.09 de la AOAC por espectrometría UV-Vis y el método respectivo del CIPAC por HPLC, con miras a garantizar que los métodos son apropiados para la determinación del plaguicida bajo las condiciones descritas, en un laboratorio químico específico. Métodos: Se siguieron los lineamientos descritos por el Ente Costarricense de Acreditación (ECA) para la verificación de parámetros de desempeño analítico en métodos normalizados. Se realizó en el Laboratorio de Control de Calidad de Agroquímicos, como requisito del último año del bachillerato en Laboratorista Químico de la Universidad de Costa Rica, Recinto de Grecia. Resultados: Los métodos por UV y HPLC demostraron ser adecuados para la determinación de paraquat, pero se recomienda someter a prueba con otros analistas, y de persistir el comportamiento, a una prueba interlaboratorial para definir el de mejor exactitud. Conclusiones: Ambas metodologías cumplen con los requerimientos establecidos por el ECA y la norma CIPAC para la validación de métodos de plaguicidas formulados, no obstante se obtuvieron diferencias significativas entre los resultados arrojados por cada una de las metodologías.

Extremes of precipitation can cause flooding and droughts which can lead to substantial damages to infrastructure and ecosystems and can result in loss of life. It is still uncertain how hydrological extremes will change with global warming as we do not fully understand the processes that cause extreme precipitation under current climate variability. Progress has been limited so far in this area due to the lack of data available to researchers. The INTENSE project, part of the with the World Climate Research Programme (WCRP)'s Grand Challenge on 'Understanding and Predicting Weather and Climate Extremes', has used a novel and fully-integrated data-modelling approach to provide a step-change in our understanding of the nature and drivers of global sub-daily precipitation extremes and change on societally relevant timescales.The first step towards achieving this was to construct a new global sub-daily precipitation dataset. The dataset contains hourly rainfall data from ~25,000 gauges across >200 territories from a wide range of sources. A rigorous, flexible quality-control algorithm has been developed to ensure that the data collected is as accurate as possible. The QC methodology combines a number of checks against neighbouring gauges, known biases and errors, and thresholds based on the Expert Team on Climate Change Detection and Indices (ETCCDI) Climate Change Indices. An open source version of the QC software will set a new standard for verifying sub-daily precipitation data.A set of global sub-daily precipitation indices have also been produced (and will be made freely available later this year) based upon stakeholder recommendations including indices that describe maximum rainfall totals and timing, the intensity, duration and frequency of storms, frequency of storms above specific thresholds and information about the diurnal cycle. The talk will discuss the major findings from the production of these new global sub-daily precipitation indices.

Climate models' outputs are affected by biases that need to be detected and adjusted to model climate impacts. Many climate hazards and climate-related impacts are associated with the interaction between multiple drivers, i.e. by compound events. So far climate model biases are typically assessed based on the hazard of interest, and it is unclear how much a potential bias in the dependence of the hazard drivers contributes to the overall bias and how the biases in the drivers interact. Here, based on copula theory, we develop a multivariate bias assessment framework, which allows for disentangling the biases in hazard indicators in terms of the underlying univariate drivers and their statistical dependence. Based on this framework, we dissect biases in fire and heat stress hazards in a suite of global climate models by considering two simplified hazard indicators, the wet-bulb globe temperature (WBGT) and the Chandler Burning Index (CBI). Both indices solely rely on temperature and relative humidity. The spatial pattern of the hazards indicators is well represented by climate models. However, substantial biases exist in the representation of extreme conditions, especially in the CBI (spatial average of absolute bias: 21 °C) due to the biases driven by relative humidity (20 °C). Biases in WBGT (1.1 °C) are small compared to the biases driven by temperature (1.9 °C) and relative humidity (1.4 °C), as the two biases compensate each other. In many regions, also biases related to the statistical dependence (0.85 °C) are important for WBGT, which indicates that well-designed physically-based multivariate bias adjustment should be considered for hazards and impacts that depend on multiple drivers. The proposed compound event-oriented evaluation of climate model biases is easily applicable to other hazard types. Furthermore, it can contribute to improved present and future risk assessments through increasing our understanding of the biases’ sources in the simulation of climate impacts.

Climatological features of observed annual maximum hourly precipitation have not been documented systematically compared to those on daily timescales due to observational limitations. Drawing from a quality-controlled database of hourly records sampling different climatic regions including the United States, Australia, the British Isles, Japan, India and peninsular Malaysia over the 1950–2016 period, we examined climatological features of annual maximum precipitation (AMP) across timescales ranging from 1-hr (AMP1−hr) to 24-hr (AMP24−hr). Our analysis reveals strong relations between the magnitude of AMP and the climatological average annual precipitation (AAP), with geographic variations in the magnitude of AMP24−hr across topographic gradients not evident in AMP1−hr. Most AMP1−hr are found to be embedded within short-duration storms (>70% of AMP1−hr are embedded within 1–5 h storms), especially in regions with low AAP and in the tropical zone. Likewise, most AMP24−hr are found to be the accumulation of a very limited number of wet hours in the 24-h period (>80% of AMP24−hr are due to storms lasting

Sub-daily rainfall observations are vital to help us understand, model and adapt to changing climate extremes. However, gauge records often have quality issues, for example due to equipment malfunctions and recording errors. This paper presents a new, open-source quality control algorithm (GSDR-QC) to identify these issues in hourly rainfall data, along with an application of the algorithm to the Global Sub-Daily Rainfall (GSDR) observational dataset. The algorithm is based on 25 quality checks, which are combined into a simple rule base to remove suspicious data. The quality checks and rule base are adaptable to help incorporate local or regional information. Comparison with manually quality-controlled gauge data shows that the procedure results in an overall improvement to the quality of the GSDR dataset. A UK case study further demonstrates the performance of the GSDR-QC procedure, while showing how region-specific data and understanding can be incorporated into the quality control process.

Objective Pregestational maternal obesity (PGMO) associates with foetoplacental vascular endothelial dysfunction and higher risk for insulin resistance in the neonate. We characterised the PGMO consequences on the insulin response of the human foetoplacental vasculature. Methods Umbilical veins were from pregnancies where the mother was with PGMO (body mass index 30–42.3 kg/m2, n = 33) or normal pregestational weight (PGMN) (body mass index 19.5–24.4 kg/m2, n = 21) with total gestational weight gain within the physiological range. Umbilical vein ring segments were mounted in a myograph for isometric force measurements. Primary cultures of human umbilical vein endothelial cells were used in passage 3. Vessel rings and cells were exposed to 1 nmol/L insulin (20 min) in the absence or presence of 100 μmol/L NG-nitro- l -arginine methyl ester (inhibitor of nitric oxide synthase, NOS). Results Vessel rings from PGMO showed reduced nitric oxide synthase-activity dependent dilation to insulin or calcitonin-gene related peptide compared with PGMN. PGMO associated with higher inhibitor phosphorylation of the insulin receptor substrate 1 (IRS-1) and lower activator phosphorylation of protein kinase B/Akt (Akt). Cells from PGMO also showed lower nitric oxide level and reduced activator serine1177 but increased inhibitor threonine495 phosphorylation of endothelial nitric oxide synthase (eNOS) and saturable transport of l -arginine. HUVECs from PGMO were not responsive to insulin. Conclusion The lack of response to insulin by the foetoplacental endothelium may result from reduced IRS-1/Akt/eNOS signalling in PGMO. These findings may result in higher risk of insulin resistance in neonates to PGMO pregnancies.

Gestational diabetes mellitus (GDM) is a disease of pregnancy associated with maternal and foetal hyperglycaemia and altered foetoplacental vascular function. Human foetoplacental microvascular and macrovascular endothelium from GDM pregnancy show increased maximal l-arginine transport capacity via the human cationic amino acid transporter 1 (hCAT-1) isoform and nitric oxide (NO) synthesis by the endothelial NO synthase (eNOS). These alterations are paralleled by lower maximal transport activity of the endogenous nucleoside adenosine via the human equilibrative nucleoside transporter 1 (hENT1) and activation of adenosine receptors. A causal relationship has been described for adenosine-activation of A2A adenosine receptors, hCAT-1, and eNOS activity (i.e. the Adenosine/l-Arginine/Nitric Oxide, ALANO, signalling pathway). Insulin restores these alterations in GDM via activation of insulin receptor A (IR-A) form in the macrovascular but IR-A and IR-B forms in the microcirculation of the human placenta. Adipokines are secreted from adipocytes influencing the foetoplacental metabolic and vascular function. Various adipokines are dysregulated in GDM, with adiponectin and leptin playing major roles. Abnormal plasma concentration of these adipokines and the activation or their receptors are involved in the pathophysiology of GDM. However, involvement of adipokines, adenosine, and insulin receptors and membrane transporters in the aetiology of this disease of pregnancy is unknown. This review focuses on the pathophysiology of insulin and adenosine receptors and l-arginine and adenosine membranes transporters giving an overview of the key adipokines leptin and adiponectin in the foetoplacental vasculature in GDM. This article is part of a Special Issue entitled: Membrane Transporters and Receptors in Pregnancy Metabolic Complications edited by Luis Sobrevia.

To sustain tumor growth, the cancer cells need to adapt to low levels of oxygen (i.e., hypoxia) in the tumor tissue and to the tumor-associated acidic microenvironment. In this phenomenon, the activation of the sodium/proton exchanger 1 (NHE1) at the plasma membrane and the hypoxia-inducible factor (HIF) are critical for the control of the intracellular pH (pHi) and for hypoxia adaptation, respectively. Interestingly, both of these mechanisms end in sustaining cancer cell proliferation. However, regulatory mechanisms of pHi in human ovary tissue and in malignant ascites are unknown. Additionally, a potential role of NHE1 in the modulation of H(+) efflux in human ovarian cancer cells is unknown. In this review, we discussed the characteristics of tumor microenvironment of primary human ovarian tumors and tumor ascites, in terms of pHi regulatory mechanisms and oxygen level. The findings described in the literature suggest that NHE1 may likely play a role in pHi regulation and cell proliferation in human ovarian cancer, potentially involving HIF2α activation. Since ovarian cancer is the fifth cause of prevalence of women cancer in Chile and is usually of late diagnosis, i.e., when the disease jeopardizes peritoneal cavity and other organs, resulting in reduced patient survival, new efforts are required to improve patient-life span and for a better understanding of the pathophysiology of the disease. The potential advantage of the use of amiloride and amiloride-derivatives for cancer treatment in terms of NHE1 expression and activity is also discussed as a therapeutic approach in human ovarian cancer.

Pregnant women that are obese may develop gestational diabetes mellitus (GDM) configuring a new metabolic condition referred to as gestational diabesity. The metabolic alterations seen in gestational diabesity include a combination of an exacerbated pro-inflammatory state and fetoplacental endothelial dysfunction. Also, gestational diabesity associates with supra-physiological extracellular concentration of adenosine in the foetoplacental blood. Since adenosine plays a central role in the inflammatory response in GDM and obesity, it is likely that this nucleoside will play a similar role in gestational diabesity. However, the effect of adenosine in the foetoplacental vasculature in this condition is not yet addressed. Adenosine exerts its biological actions via four adenosine receptors. Activation of A

Obesity and type 2 diabetes mellitus (T2DM) are diseases associated with hypertension and metabolic alterations. A significant group of patients present both obesity and T2DM, a condition defined as diabesity. One of the metabolic features in these conditions is the clinical presentation of insulin resistance. Several tissues, including the liver, skeletal muscle, and vasculature, and patients with T2DM, gestational diabetes, and obesity show insulin resistance. The vascular effect of insulin, including vasodilation, is mainly mediated by the generation of nitric oxide. Several mechanisms are proposed to elucidate the origin of insulin resistance; nevertheless, a common finding is the endothelial dysfunction in these diseases. Endothelial cells from subjects with obesity show reduced nitric oxide synthesis, an effect that is unaltered by insulin. Individuals with T2DM show a misbalance between the synthesis, release, and biological actions of vasodilators and vasoconstrictors such as nitric oxide and endothelin-1. However, whether these mechanisms are involved in the vascular alterations seen in patients with diabesity is unclear. In this review, we discussed the modifications on insulin signalling, insulin resistance in obesity and T2DM, and the reported changes in signalling pathways in diabesity.

Obesity associates with the endoplasmic reticulum (ER) stress-induced endothelial dysfunction. Pregnant women with pre-pregnancy maternal obesity (PGMO) may transfer this potential risk to their offspring; however, whether ER stress occurs and associates with foetoplacental endothelial dysfunction in PGMO is unknown. We studied the L-arginine transport and nitric oxide (NO) synthesis in human umbilical vein endothelial cells (HUVECs) from women with PGMO or with a normal pre-pregnancy weight. We analysed the expression and activation of the ER stress sensors protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 alpha (IRE1 alpha), and activating transcription factor 6 (ATF6). PGMO associated with lower endothelial NO synthase activity due to increased Thr(495)-inhibitor and decreased Ser(1177)-stimulator phosphorylation. However, higher expression and activity of the human cationic amino acid transporter 1 was found. PGMO caused activation of PERK and its downstream targets eukaryotic initiation factor 2 (eIF2 alpha), C/EBP homologous protein 10 (CHOP), and tribbles-like protein 3 (TRB3). Increased IRE1 a protein abundance (but not its phosphorylation or X-box binding protein 1-mRNA splicing) and increased c-Jun N-terminal kinase 1 phosphorylation was seen in PGMO. A preferential nuclear location of the activating transcription factor 6 (ATF6) was found in HUVECs from PGMO. All the changes seen in PGMO were blocked by TUDCA but unaltered by tunicamycin. Thus, PGMO may determine a state of ER stress via upregulation of the PERK-eIP2 alpha-CHOP-TRB3 axis signalling in HUVECs. This phenomenon results in foetoplacental vascular endothelial dysfunction at birth.

Insulin resistance is characteristic of pregnancies where the mother shows metabolic alterations, such as preeclampsia (PE) and gestational diabetes mellitus (GDM), or abnormal maternal conditions such as pregestational maternal obesity (PGMO). Insulin signalling includes activation of insulin receptor substrates 1 and 2 (IRS1/2) as well as Src homology 2 domain-containing transforming protein 1, leading to activation of 44 and 42 kDa mitogen-activated protein kinases and protein kinase B/Akt (Akt) signalling cascades in the human foetoplacental vasculature. PE, GDM, and PGMO are abnormal conditions coursing with reduced insulin signalling, but the possibility of the involvement of similar cell signalling mechanisms is not addressed. This review aimed to determine whether reduced insulin signalling in PE, GDM, and PGMO shares a common mechanism in the human foetoplacental vasculature. Insulin resistance in these pathological conditions results from reduced Akt activation mainly due to inhibition of IRS1/2, likely due to the increased activity of the mammalian target of rapamycin (mTOR) resulting from lower activity of adenosine monophosphate kinase. Thus, a defective signalling via Akt/mTOR in response to insulin is a central and common mechanism of insulin resistance in these diseases of pregnancy. In this review, we summarise the cell signalling mechanisms behind the insulin resistance state in PE, GDM, and PGMO focused in the Akt/mTOR signalling pathway in the human foetoplacental endothelium. Unión Europea Framework Grant Agreement no. 295185–EULAMDIMA

Cell-to-cell communication happens via diverse mechanisms including the synthesis, release and transfer to target cells of extracellular vesicles (EVs). EVs include nanovesicles (i.e., exosomes) and microvesicles, including apoptotic bodies. The amount and cargo of released EVs, which consist of microRNAs (miRNAs), mRNA, proteins, DNA, among other molecules, are altered in obesity and diabetes mellitus. EVs from these diseases show with altered cargo including several miRNAs and the enrichment with molecules involved in inflammation, immune efficiency, and cell activation. The role of EVs in obesity regards with adipocytes-released vesicles that may end in a systemic insulin resistance. In diabetes mellitus, the exosomes cargo may signal to transform a normal phenotype into a diabetic phenotype in endothelial cells. The evidence of EVs as modulators of cell function is increasing; however, it is still unclear whether exosomes or microvesicles are a trustable and useful marker for the diagnose or early detection of obesity or diabetes mellitus. In this review, we summarise the reported information regarding EVs involvement in obesity, T1 and T2 diabetes mellitus, and gestational diabetes mellitus. We emphasise the fact that studies addressing a potential effect of obesity or diabetes mellitus on cell function and the severity of the diseases are done in patients suffering simultaneously with both of these diseases, i.e., diabesity. Unfortunately, the lack of information regarding the biological effects and the potential involved mechanisms makes difficult to understand the role of the EVs as a marker of these and perhaps other diseases.

Human umbilical vein endothelial cells (HUVECs) from diet treated women with gestational diabetes mellitus (GDMd) show reduced C/EBP homologous protein 10 (hCHOP)-dependent human equilibrative nucleoside transporter 1 (hENT1) expression. Some patients wit