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Abstract Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinases, especially of Ret and the FGF receptors. As such, they play distinct and overlapping roles in embryo morphogenesis and are considered to be tumor suppressors in adult life. Genetic experiments in mice have defined in great detail the role of these genes during embryonic development, however their function in adult mice is less clearly established. Here we generate adult-onset, whole body Spry1/2/4 triple knockout mice. Tumor incidence in triple mutant mice is comparable to that of wild type littermates of up to one year of age, indicating that Sprouty loss per se is not sufficient to initiate tumorigenesis. On the other hand, triple knockout mice do not gain weight as they age, show less visceral fat, and have lower plasma glucose levels than wild type littermates, despite showing similar food intake and slightly reduced motor function. They also show alopecia, eyelid inflammation, and mild hyperthyroidism. Finally, triple knockout mice present phosphaturia and hypophosphatemia, suggesting exacerbated signaling downstream of FGF23. In conclusion, triple knockout mice develop a series of endocrine abnormalities but do not show increased tumor incidence.

In semi-arid irrigated environments, agricultural drainage is at the heart of three agro-environmental issues: it is an indicator of water productivity, it is the main control to prevent soil salinization and waterlogging problems, and it is related to the health of downstream ecosystems. Crop water balance models combined with subsurface models can estimate drainage quantities and dynamics at various spatial scales. However, such models' precision (capacity of a model to fit the observed drainage using site-specific calibration) and accuracy (capacity of a model to approximate observed drainage using default input parameters) have not yet been assessed in irrigated areas. To fill the gap, this study evaluates four parsimonious drainage models based on the combination of two surface models (RU and SAMIR) and two subsurface models (Reservoir and SIDRA) with varying complexity levels: RU-Reservoir, RU-SIDRA, SAMIR-Reservoir, and SAMIR-SIDRA. All models were applied over two sub-basins of the Algerri–Balaguer irrigation district, northeastern Spain, equipped with surface and subsurface drains driving the drained water to general outlets where the discharge is continuously monitored. Results show that RU-Reservoir is the most precise (average KGE (Q0.5) of 0.87), followed by SAMIR-Reservoir (average KGE (Q0.5) of 0.79). However, SAMIR-Reservoir is the most accurate model for providing rough drainage estimates using the default input parameters provided in the literature.

When irrigation is introduced in a region, it adds salts and mobilizes those already present in the soil, changing the soil-plant-atmosphere continuum. These changes may lead to higher salt loads in the drainage water which, in turn, can have an impact on waters further downstream. Knowing the dynamics of these loads at the sub-basin scale is key to accounting for the possible impact that irrigation may have and to determining what improvements could be applied. This study aimed to characterise the different salt types present and to investigate drainage salt loads and their dependence upon irrigation input and their implications in irrigation management in a new, and well-managed, 8000 ha irrigation district located in the Ebro basin, NE Spain. In addition, it is relevant to highlight that the Ebro basin suffered a period of significant drought in 2023. As a result, irrigation restrictions were applied in many irrigation districts. We sought to investigate how these reductions influenced irrigation return flows and salt discharges within a selected irrigation district. The present study was undertaken during the irrigation periods of 2021, 2022, and 2023. We monitored water inputs and outputs in two representative sub-basins belonging to the Algerri-Balaguer irrigation district (Ebro basin, NE Spain). We also analysed water inputs and outputs in order to characterise and establish the salt balances in both of the sub-basins that we studied. Our results showed that during 2023, a reduction in irrigation delivery of 31% led to a reduction in drainage volume of 73%, resulting in a decrease in salt exports through drainage of 70%. These data revealed that the application of irrigation restrictions not only led to an increased availability of downstream water resources, but also to a decrease in drainage volume and salt load, resulting in an improvement in irrigation management by farmers. However, it should also be underlined that this drastic reduction in irrigation was, in turn, responsible for a reduction in yield. Re-utilising drainage waters and/or improving irrigation management at the field scale may help to find this point of balance in areas with high water demands.

Abstract Background The COVID-19 pandemic had and still have a major impact on adolescent mental health and consequently on suicidal behavior. However, few studies have investigated whether the pandemic has changed the patterns and the triggers of suicidality peaks in adolescents, e.g., seasonal patterns or family conflicts. We hypothesized that the pandemic modified suicidality rates: an increment of suicide attempts would be observed in the first semester of the academic year during COVID-19 pandemic compared to the same period of previous academic year; and the precipitating factors would be more related to social stressors during the pandemic school year. Methods A retrospective cross-sectional study was conducted to assess the precipitating factors, also including school-related factors and cognitive skills, of adolescent suicide attempters occurred in the first and second semesters of the year before the pandemic lockdown (study periods 1 and 2) and the year after (study periods 3 and 4). Results The sample consisted of 85 adolescents aged between 12 and 17 recruited consecutively from March 2019 to March 2021 at emergency ward because of suicide attempt. Forty-eight adolescents (55.3% of the sample) were attended before the lockdown (pre-pandemic group) and 38 (44.7%) the year after. The results showed a higher proportion of female suicide attempters in period 4 (Sept 2020-Feb 2021) respect to period 3 (Mar 2020-Aug 2020), i.e., pandemic semesters compared with the increment observed between period 2 and 1 (prepandemic semesters; Fisher’s exact test = 4.73; p = 0.026). The multinomial regression models showed a significant effect in the frequency of adolescents who attempted suicide (ratio χ2 = 15.19, p = 0.019), accounted by the differences between period 4 (Sept 2020-Feb 2021) and period 1 (Mar 2019-Aug 2019), with depressive symptoms being a significant contributing factor (Exp(b) = 0.93; p = 0.04). Additionally, social triggers and age were found to be significant risk factors for suicide attempts in the first semester of the pandemic academic year (period 4) compared to the same semester of the pre-pandemic year (period 2; Exp(b) = 0.16, p = 0.01, and Exp(b) = 1.88, p = 0.006, respectively). Conclusions During the pandemic, the decrement between first and second semester of the number of females attempting suicide was more pronounced than in the prepandemic school year -though this findings lacked statistical power due to very limited sample size-. Change in the frequency of adolescent attempting suicide in the different school periods was associated with greater severity of depressive symptoms. Social relations in back-to-school after the lockdown were also associated with the number of adolescents attempting suicide.

Abstract Genes of the Sprouty family (Spry1-4) restrain signaling by certain receptor tyrosine kinases. Consequently, these genes participate in several developmental processes and function as tumor suppressors in adult life. Despite these important roles, the biology of this family of genes still remains obscure. Here we show that Sprouty proteins are general mediators of cellular senescence. Induction of cellular senescence by several triggers in vitro correlates with upregulation of Sprouty protein levels. More importantly, overexpression of Sprouty genes is sufficient to cause premature cellular senescence, via a conserved N-terminal tyrosine (Tyrosine 53 of Sprouty1). Accordingly, fibroblasts from knockin animals lacking that tyrosine escape replicative senescence. In vivo, heterozygous knockin mice display delayed induction of cellular senescence during cutaneous wound healing and upon chemotherapy-induced cellular senescence. Unlike other functions of this family of genes, induction of cellular senescence appears to be independent of activation of the ERK1/2 pathway. Instead, we show that Sprouty proteins induce cellular senescence upstream of the p38 pathway in these in vitro and in vivo paradigms.

Abstract Background Since 2008, children in Catalonia (Spain) have suffered a period of great economic deprivation. This situation has generated broad-ranging health inequalities in a variety of diseases. It is not known how these inequalities have changed over time. The aim of the present study is to determine trends in inequalities over this period in ten relevant diseases in children according to sex and age. Methods A retrospective cross-sectional population-based study of all children under 15 years old resident in Catalonia during the 2014–2021 period (over 1.2 million children/year) and of their diagnoses registered by the Catalan Health System. Health inequalities were estimated by calculating the relative index of inequality and time trends using logistic regression models. Interaction terms were added to test for the effects of sex on time trends. Results Increasing significant temporal trends in inequalities were shown for both sexes in almost all the diseases or adverse events studied (asthma, injuries, poisoning, congenital anomalies, overweight and obesity), in mood disorders in boys, and in adverse birth outcomes in girls. Adjustment and anxiety and mood disorders in girls showed a decreasing temporal trend in inequalities. More than half of the diseases and adverse events studied experienced significant annual increases in inequality. Poisoning stood out with an average annual increase of 8.65% [4.30, 13.00], p ≤ 0.001 in boys and 8.64% [5.76, 11.52], p ≤ 0.001) in girls, followed by obesity with increases of 5.52% [4.15, 6.90], p =

The Wolffian ducts (WD) are paired epithelial tubules central to the development of the mammalian genitourinary tract. Outgrowths from the WD known as the ureteric buds (UB) generate the collecting ducts of the kidney. Later during development, the caudal portion of the WD will form the vas deferens, epididymis and seminal vesicle in males, and will degenerate in females. While the genetic pathways controlling the development of the UB are firmly established, less is known about those governing development of WD portions caudal to the UB. Sprouty proteins are inhibitors of receptor tyrosine kinase (RTK) signaling in vivo. We have recently shown that homozygous mutation of a conserved tyrosine (Tyr53) of Spry1 results in UB defects indistinguishable from that of Spry1 null mice. Here, we show that heterozygosity for the Spry1 Y53A allele causes caudal WD developmental defects consisting of ectopically branched seminal vesicles in males and persistent WD in females, without affecting kidney development. Detailed analysis reveals that this phenotype also occurs in Spry1+/- mice but with a much lower penetrance, indicating that removal of tyrosine 53 generates a dominant negative mutation in vivo. Supporting this notion, concomitant deletion of one allele of Spry1 and Spry2 also recapitulates the genital phenotype of Spry1Y53A/+ mice with high penetrance. Mechanistically, we show that unlike the effects of Spry1 in kidney development, these caudal WD defects are independent of Ret signaling, but can be completely rescued by lowering the genetic dosage of Fgf10. In conclusion, mutation of tyrosine 53 of Spry1 generates a dominant negative allele that uncovers fine-tuning of caudal WD development by Sprouty genes.

The need to feed an increasing population while limiting the environmental impact of agriculture is currently one of the greatest challenges relating to the food chain. One of the key factors involved in doing this is irrigation, which has a downstream impact that can be minimised if nutrient and water management are efficiently undertaken. The objective of this study was to determine which irrigation management improvements can be done at field scale in modern irrigated areas to reduce its irrigation return flow impact. The study was conducted in the Noguera Ribagorçana River basin, in NE Spain, where almost 6000 ha of land were brought into irrigation from 2000 to 2009. We based our study on a water quality dataset, measured in four different sites along a 29 km2 stretch of the river over a period of 20 years. Our results show an increase in nitrate (from 1.7 mg·L−1 to 10.5 mg·L−1) and salt concentrations (electrical conductivity from 297 to 675 µS·m−1) in the downstream course of the river compared to the most upstream monitoring site. That was exclusively associated with the irrigation return flows from the newly irrigated area. The highest nitrate and salt concentrations are found during the non-irrigation season which corresponds to the local rainy season. To reduce this impact, better irrigation management is required. Autumn leaching could be lowered by reducing irrigation volume applied during the final weeks of crop cycles in order to allow the soil to retain the volume of water received from rainfall. To deal with this issue, we propose a methodology based on soil moisture to determine the end of the irrigation season. In this way, the impact on ecosystems located further downstream would be reduced while crop yields and productivity in the area could be maintained.

Irrigation is the most water consuming activity in the world. Knowing the timing and amount of irrigation that is actually applied is therefore fundamental for water managers. However, this information is rarely available at all scales and is subject to large uncertainties due to the wide variety of existing agricultural practices and associated irrigation regimes (full irrigation, deficit irrigation, or over-irrigation). To fill this gap, we propose a two-step approach based on 15 m resolution Sentinel-1 (S1) surface soil moisture (SSM) data to retrieve the actual irrigation at the weekly scale over an entire irrigation district. In a first step, the S1-derived SSM is assimilated into a FAO-56-based crop water balance model (SAMIR) to retrieve for each crop type both the irrigation amount (Idose) and the soil moisture threshold (SMthreshold) at which irrigation is triggered. To do this, a particle filter method is implemented, with particles reset each month to provide time-varying SMthreshold and Idose. In a second step, the retrieved SMthreshold and Idose values are used as input to SAMIR to estimate the weekly irrigation and its uncertainty. The assimilation approach (SSM-ASSIM) is tested over the 8000 hectare Algerri-Balaguer irrigation district located in northeastern Spain, where in situ irrigation data integrating the whole district are available at the weekly scale during 2019. For evaluation, the performance of SSM-ASSIM is compared with that of the default FAO-56 irrigation module (called FAO56-DEF), which sets the SMthreshold to the critical soil moisture value and systematically fills the soil reservoir for each irrigation event. In 2019, with an observed annual irrigation of 687 mm, SSM-ASSIM (FAO56-DEF) shows a root mean square deviation between retrieved and in situ irrigation of 6.7 (8.8) mm week-1, a bias of +0.3 (−1.4) mm week-1, and a Pearson correlation coefficient of 0.88 (0.78). The SSM-ASSIM approach shows great potential for retrieving the weekly water use over extended areas for any irrigation regime, including over-irrigation.

The aim of this study is to carry out a taxonomic revision of the groups Calamistratum and Geraniodorum of the genus Inosperma sect. Inosperma in Europe. For this purpose, a multigenic phylogenetic analysis was carried out using the ITS, LSU, RPB1 and RPB2 markers, covering a total of 111 sequences, including those generated from the existing type-material collections. This analysis led to the recognition of nine clades or terminal groups for the European continent, correlating with nine morphological species. Three of them, I. calamistratum, I. neohirsutum sp. nov. and I. turietoense sp. nov., are distributed in humid and temperate forests, whereas I. geminum sp. nov., I. geraniodorum, I. gracilentum sp. nov., I. praetermissum comb. nov., I. subhirsutum and I. veliferum seem to be restricted to the colder altimontane, boreal and alpine climates. It is concluded that the study of morphological and ecological characteristics allows the recognition of species without the need for an often-subjective interpretation of organoleptic characteristics. Inocybe hirsuta is considered a synonym of Inosperma calamistratum, Inosperma praetermissum as a different species from I. calamistratum, and Inocybe geraniodora var. gracilenta f. salicis-herbaceae as a synonym of I. praetermissum. Four new species and one new combination are proposed. A key for the recognition of the European species is provided. Illustrations and photographs of macro- and micromorphological characters and SEM spores of all species are presented.

Introduction: Biological and sociocultural factors may lead to a significant gender bias in the treatment of major depression and thus contribute to accentuating gender inequalities. However, the influence of the general practitioner’s (GP’s) sex on the prescription of antidepressants has not been adequately assessed in previous work and remains unclear. This retrospective cohort study aims to determine the influence of GP and patient sex on the treatment of major depression.Methods: The study population comprised 87,629 patients (33.56% male patients and 66.44% female patients) aged over 15 years newly diagnosed with major depression recorded between 2017 and 2019 in Catalonia, Spain. Logistic regression models were used to evaluate the effect of GP sex on the therapeutic strategy (i.e., whether antidepressants were prescribed at the first diagnostic visit). Cox proportional hazards models and survival analyses were conducted to compare, according to GP and patient sex, the probability that a patient would be prescribed an antidepressant at any time during the study period. Finally, a multiple linear regression analysis was performed to assess the pharmacological intensity of the treatment [monthly fluoxetine-equivalent defined daily dose (DDD)].Results: Female patients were more likely to be prescribed an antidepressant at the time of diagnosis, both by male [OR = 1.11, 95% CI = (1.05, 1.17), p

Abstract Phosphatase and TENsin homolog (Pten) and p53 are two of the most frequently mutated tumor suppressor genes in endometrial cancer. However, the functional consequences and histopathological manifestation of concomitant p53 and Pten loss of function alterations in the development of endometrial cancer is still controversial. Here, it is demonstrated that simultaneous Pten and p53 deletion is sufficient to cause epithelial to mesenchymal transition phenotype in endometrial organoids. By a novel intravaginal delivery method using HIV1 trans‐activator of transcription cell penetrating peptide fused with a Cre recombinase protein (TAT‐Cre), local ablation of both p53 and Pten is achieved specifically in the uterus. These mice developed high‐grade endometrial carcinomas and a high percentage of uterine carcinosarcomas resembling those found in humans. To further demonstrate that carcinosarcomas arise from epithelium, double Pten/p53 deficient epithelial cells are mixed with wild type stromal and myometrial cells and subcutaneously transplanted to Scid mice. All xenotransplants resulted in the development of uterine carcinosarcomas displaying high nuclear pleomorphism and metastatic potential. Accordingly, in vivo CRISPR/Cas9 disruption of Pten and p53 also triggered the development of metastatic carcinosarcomas. The results unfadingly demonstrate that simultaneous deletion of p53 and Pten in endometrial epithelial cells is enough to trigger epithelial to mesenchymal transition that is consistently translated to the formation of uterine carcinosarcomas in vivo.

Abstract Introduction Gender bias in healthcare is understood as a misconception of the differences between males and females that may generate healthcare disparities and discrimination against one sex. However, is not well known how this implicit bias is manifested in pediatric clinical praxis. Thus, the goal of this study is to explore and analyse the attitudes of health personnel toward a possible gender bias in pediatric care in Catalonia. Methods We undertake a descriptive and exploratory study applying a qualitative research methodology based on hermeneutic phenomenology and Grounded Theory using the focus group technique. The opinions collected were classified into four categories and 22 subcategories, and subsequently analyzed. Results Three main ideas stood out regarding situations that might be affected by gender bias: (1) attitudes of health personnel and perceptions with regard to mental health problems and (to a lesser extent) to physical health problems; (2) the role of the child's family and the professional's assessment of this role; and (3) the professional's attention to children of the opposite sex, especially in the case of genital examinations. Discussion The results stand out that differential attitudes depending on the gender of the child have been observed in clinical practice in pediatrics, which may have an impact on health inequality. Hence, academic training that includes the study and prevention of implicit biases in professional activity, campaigns aimed at the general population on how to detect implicit biases and promoting gender equity in education, should help to avoid the negative consequences of these misconceptions.