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The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential energy source for normal function of cardiac muscle during each beat, as it powers ion transport, intracellular Ca2+ handling, and actin-myosin cross-bridge cycling. Despite this, the impact of excitation-contraction coupling on the intracellular ATP concentration ([ATP]i) in myocytes is poorly understood. Here, we conducted real-time measurements of [ATP]i in ventricular myocytes using a genetically encoded ATP fluorescent reporter. Our data reveal rapid beat-to-beat variations in [ATP]i. Notably, diastolic [ATP]i was

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

Introduction and objectives: To estimate the frequency of patients with diagnoses associated with life-limiting conditions (LLCs) or complex chronic conditions (CCCs). Methods: Retrospective mixed population-based and hospital-based cohort study. Study universe consisted of the population aged less than 18 years of an autonomous community in Spain in the 2001–2021 period; the cases were patients admitted to hospital with a diagnosis associated with LLC or CCC during this period. We estimated age-adjusted annual prevalences and analysed changes in trends using joinpoint regression. Results: The prevalence of LLCs increased significantly from 20.7 per 10 000 inhabitants under 18 years in 2001 to 51.3 per 10 000 in 2019. There was also a significant increase in CCCs from 39.9 per 10 000 in 2001 to 54.4 per 10 000 in 2019. The prevalence of patients with any of these conditions rose from 45 per 10 000 in 2001 to 86.8 per 10 000 in 2019; 30.3% of these patients had conditions of both types. There was a turning point in this increasing trend between 2019 and 2020, coinciding with the COVID-19 pandemic. Conclusions: The prevalence of patients requiring specialized care has increased progressively in the last 20 years, similar to what has happened in other countries. The magnitude of the affected population must be taken into account when planning specialized paediatric palliative care and complex chronic care services. Resumen: Introducción y objetivos: Estimar la frecuencia de pacientes con diagnósticos asociados a condiciones limitantes para la vida (CLV) o condiciones crónicas complejas (CCC). Métodos: Estudio retrospectivo de cohortes de base mixta poblacional-hospitalaria. La población de estudio fue la población menor de 18 años de una comunidad autónoma española desde 2001 a 2021. Los casos fueron los pacientes con algún ingreso hospitalario con algún diagnóstico asociado a CLV o CCC. Estimamos las prevalencias anuales ajustadas por edad y los cambios de tendencia mediante regresión de Joinpoint. Resultados: La prevalencia de CLV ascendió de forma significativa desde un 20,7 por 10 000 en 2001 hasta un 51,3 por 10 000 en 2019. Para CCC también ha tenido lugar un aumento significativo desde un 39,9 por 10 000 en 2001 a un 54,4 por 10 000 en 2019. Las prevalencias de pacientes con alguna de estas condiciones ascendieron desde un 45 por 10 000 en 2001 hasta un 86,8 por 10 000 en 2019; un 30,3% de pacientes tenían ambas condiciones. Se produjo un punto de inflexión en esa tendencia creciente entre 2019 y 2020, coincidiendo con la pandemia COVID-19. Conclusiones: La prevalencia de pacientes subsidiarios de precisar cuidados especiales ha ascendido progresivamente en los últimos 20 años, de forma similar a como ha ocurrido en otros países. La magnitud de la población afectada ha de ser tenida en cuenta para la planificación de servicios especializados pediátricos de cuidados paliativos y crónicos complejos.

Abstract Child pornography—better known as child sexual abuse material (CSAM)—represents a severe form of exploitation and victimization of children, leaving the victims with emotional and physical trauma. In this study, we aim to analyze local patterns of CSAM consumption across 1341 French communes in 20 metropolitan regions of France between March 16 to May 31, 2019 using fine-grained mobile traffic data of Tor network-related web services. We estimate that approx. 0.08% of Tor mobile download traffic observed in France is linked to the consumption of CSAM by correlating it with local-level temporal porn consumption patterns. This compares to 0.19% of what we conservatively estimate to be the share of CSAM content in global Tor traffic. In line with existing literature on the link between sexual child abuse and the consumption of image-based content thereof, we observe a positive and statistically significant effect of our CSAM consumption estimates on the reported number of victims of sexual violence and vice versa, which validates our findings, after controlling for a set of geographically disaggregated features including socio-demographic characteristics, voting behavior, nearby points of interest and Google Trends queries. While this is a first, exploratory attempt to look at CSAM from a spatial epidemiological angle, we believe this research provides public health officials with valuable information to prioritize target areas for public awareness campaigns as another step to fulfill the global community’s pledge to target 16.2 of the sustainable development goals: “end abuse, exploitation, trafficking and all forms of violence and torture against children".

Abstract Maintaining both high sensitivity and large figure of merit (FoM) is crucial in regard to the performance of optical devices, particularly when they are intended for use as biosensors with extremely low limit of detection (LoD). Here, a stack of nano‐assembled layers in the form of 1D photonic crystal, deposited on D‐shaped single‐mode fibers, is created to meet these criteria, resulting in the generation of Bloch surface wave resonances. The increase in the contrast between high and low refractive index (RI) nano‐layers, along with the reduction of losses, enables not only to achieve high sensitivity, but also a narrowed resonance bandwidth, leading to a significant enhancement in the FoM. Preliminary testing for bulk RI sensitivity is carried out, and the effect of an additional nano‐layer that mimics a biological layer where binding interactions occur is also considered. Finally, the biosensing capability is assessed by detecting immunoglobulin G in serum at very low concentrations, and a record LoD of 70 aM is achieved. An optical fiber biosensor that is capable of attaining extraordinarily low LoD in the attomolar range is not only a remarkable technical outcome, but can also be envisaged as a powerful tool for early diagnosis of diseases.

The main objective of the study was to analyze the relationship between level of competition and declarative and procedural knowledge in young volleyball players. We propose a descriptive/correlational study involving 219 players aged between 14 and 16 years. The level of competition (scholar, regional and national) was the independent variable. Whereas, dependent variables were the two types of knowledge, declarative and procedural, which were measured by filling in two questionnaires. The results show significant differences in knowledge according to the level of competition. Players who participated in national competition show higher levels of declarative and procedural knowledge than those who compete in regional and scholar level. These results reinforce the idea that is the quality of the competition, in which athletes participate, a key factor in the development of the two types of knowledge considered in the investigation

CaV1.2 channels are critical players in cardiac excitation-contraction coupling, yet we do not understand how they are affected by an important therapeutic target of heart failure drugs and regulator of blood pressure, angiotensin II. Signaling through Gq-coupled AT1 receptors, angiotensin II triggers a decrease in PIP2, a phosphoinositide component of the plasma membrane (PM) and known regulator of many ion channels. PIP2 depletion suppresses CaV1.2 currents in heterologous expression systems but the mechanism of this regulation and whether a similar phenomenon occurs in cardiomyocytes is unknown. Previous studies have shown that CaV1.2 currents are also suppressed by angiotensin II. We hypothesized that these two observations are linked and that PIP2 stabilizes CaV1.2 expression at the PM and angiotensin II depresses cardiac excitability by stimulating PIP2 depletion and destabilization of CaV1.2 expression. We tested this hypothesis and report that CaV1.2 channels in tsA201 cells are destabilized after AT1 receptor-triggered PIP2 depletion, leading to their dynamin-dependent endocytosis. Likewise, in cardiomyocytes, angiotensin II decreased t-tubular CaV1.2 expression and cluster size by inducing their dynamic removal from the sarcolemma. These effects were abrogated by PIP2 supplementation. Functional data revealed acute angiotensin II reduced CaV1.2 currents and Ca2+ transient amplitudes thus diminishing excitation-contraction coupling. Finally, mass spectrometry results indicated whole-heart levels of PIP2 are decreased by acute angiotensin II treatment. Based on these observations, we propose a model wherein PIP2 stabilizes CaV1.2 membrane lifetimes, and angiotensin II-induced PIP2 depletion destabilizes sarcolemmal CaV1.2, triggering their removal, and the acute reduction of CaV1.2 currents and contractility.

AbstractThe purpose of this study was to modify the verbal behavior of volleyball coaches during competition. Three beginner volleyball coaches were included in a formative program that included supervisory feedback plus systematic analysis of the coaches´ verbal feedback, as well as the coaches´ own observations and self-corrections of their behavior during the competitive season. The outcome variable of interest was the verbal behavior of the coach during timeouts during games, with consideration given for two specific dimensions of behavior: the type of information provided to the team and the team to which the coach made reference. The results revealed a change in the verbal behavior of the coaches, which was principally demonstrated in an increase in amount of tactical information and information provided about the opponent.ResumenEl propósito de este estudio fue modificar la conducta verbal del entrenador de voleibol durante la competición. Tres entrenadores de voleibol fueron sometidos a un programa formativo (feedback de supervisión con análisis sistemático de la conducta verbal del entrenador, y visionado de la actuación) durante una temporada de competición. La variable dependiente de la investigación fue la conducta verbal del entrenador durante los tiempos muertos, considerándose dos dimensiones en la misma: tipo de información, equipo al que hace referencia la información. Los resultados obtenidos muestran una modificación en la conducta verbal de los entrenadores, manifestada fundamentalmente en el incremento de información táctica y sobre el equipo contrario.

Abstract Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

ABSTRACT: introduction: The main goal in this study was to know the efficacy of treatment with Secnidazole in schoolchildren acting as asymptomatic carriers of Giardia lumblia and Entamoela histolytica and also to evaluate its toleration. Materials and Methods: A total of 50 children with parasitic disease (from 53 children with Entamoeba histolytica and/or Giardia lamblia) were chosen for the study, with ages ranking from 5 to 14, of either gender, to whom the drug was administered, and coproparasitological control tests were performed to them at third day of therapy. A question form was used to evaluate oral toleration to the drug. Result: From 53 cases studied, the protozoal ratio was as follows: Giardia lamblia 66.03%, followed by Entamoeba histolytica, 33.97 %. Parasitological effectiveness of Secnidazole against Gíardia lamblía was 100%, and against Entamoeba histolytica was 95.45 %. Only one carrier (4.55 %) did not respond to treatment. The drug had a good toleration in 50% of the cases. Most frequent symptoms were hyporexy, headache, abdominal discomfort/pair, dizziness, nausea, vomiting, diarrhea, drowsiness, taste sense anomal1e and itching. Conclusion: Efficacy and a relatively good oral toleration to Secnidazole was demonstrated in this study. Parasite absence was demonstrated after three days of trea1ment. RIESUMEN: Introducción: El propósito de la investigación es conocer la eficacia del Secnidazol en el tratamiento de escolares asintomáticos portadores de Giardia lamblia y/o Entamoeba histolytica, así como el evaluar su tolerancia. Material y métodos: Se escogieron 50 niños parasitados (totalizando 53 casos con Entamoeba histolytica y/o Giardia lamblia), con edades comprendidas entre 5 y 14 años, de uno u otro sexo, a quienes se les administró el medicamento y tres días después se realizaron exámenes coproparasitológicos controles. La tolerancia del medicamento se evaluó mediante encuesta. Resultados: De 53 casos parasitados, la relación de protozoarios fue: Giardia lamblia (66,03%) seguidos de Entamoeba histolylica (33,97%). La efectividad parasitológica del Secnidazol contra Giardia lamblia fue del 100% y de Entamoeba histolytica de 95,45%. Se obtuve un solo caso portador que no respondió al tratamiento (4,55%). El medicamento fue bien tolerado en el 50% de los casos. Los síntomas más frecuentes fueron: hiporexia, cefalea, dolor abdominal, mareos, náuseas, vómitos, diarrea, fatiga, alteración del gusto y prurito. Conclusiones: La eficacia y la relativamente buena tolerancia del Secnidazol fue demostrada en d presente estudie. Se obtuvo cura parasitológica al tercer día de administrado el medicamento.

The results presented here show for the first time the experimental demonstration of the fabrication of lossy mode resonance (LMR) devices based on perovskite coatings deposited on planar waveguides. Perovskite thin films have been obtained by means of the spin coating technique and their presence was confirmed by ellipsometry, scanning electron microscopy, and X-ray diffraction testing. The LMRs can be generated in a wide wavelength range and the experimental results agree with the theoretical simulations. Overall, this study highlights the potential of perovskite thin films for the development of novel LMR-based devices that can be used for environmental monitoring, industrial sensing, and gas detection, among other applications.

Environmental-related hazards are a global problem; consequently, an Environmental Worry Index (EWI) was developed; however, the psychometric properties of this scale in the Spanish population are unavailable.

Several reports have provided evidence that there are genetic variants of genes such as MSTN, BDRKB2, ACTN3 and ADRB2 that are involved in a better response to adaptation during resistance or strength training, while other genes such as GRB14, AGT and END1 are reported to be associated with the risk of suffering from some diseases such as diabetes, hypertension or obesity. A cross-sectional study from a Mexican Mestizo population was performed to estimate the frequency of 10 gene variants in 8 genes involved in athletic performance or chronic degenerative diseases, MSTN (rs1805085, rs1805086), BDKRB2 (rs1799722), FST (rs1423560), ACTN3 (rs1815739), ADRB2 (rs1042713, rs1042714), GRB14 (rs8192673), AGT (rs699) and EDN1 (rs5370), and to compare frequencies from 26 populations reported in the Database of 1000 Genomes project. Genotype frequencies fitted the Hardy–Weinberg equilibrium, except for MST rs1805086 and FST rs1423560, and our study revealed significant differences in the distribution of frequencies of some of these gene variants among populations reported in the 1000 Genomes Project. Our findings provide insights regarding the genetic background of our population, and future case–control studies can be carried out with more accurate sample sizes for genetic association studies. Our results may be also useful in recognizing the roles and mechanisms contributing to athletic performance and/or chronic degenerative diseases in Mexicans.

Background: illegal drugs significantly contribute to global health issues, with health complications often occurring not only in regular users with Substance Use Disorders (SUDs) but also in first-time and occasional users. Methods: this study examines five clinical cases from a public hospital in Ibiza, Spain, where patients presented with acute psychiatric symptoms due to recreational drug use. Results: Contrary to previous studies on SUDs, our patients typically had higher education levels and stable employment. Most of them used multiple substances, with cannabis, cocaine, and alcohol being the most frequently used. There was also a common occurrence of consuming drugs with uncertain contents. Upon admission, typical symptoms included aggression, hallucinations, mood swings, and disorientation in time and space. Conclusions: Our findings underscore the significant mental health risks posed by illicit drugs, even for individuals with no prior psychiatric history. Factors like the drug’s potency, frequency and amount of use, past mental health issues, personality traits, and previous traumatic experiences might influence the onset of these symptoms.

Summary: The distinct folding accompanied by its polymorphic character renders DNA G-quadruplexes promising biomolecular building blocks to construct novel DNA-based and supramolecular assemblies. However, the highly polar nature of DNA limits the use of G-quadruplexes to water as a solvent. In addition, the archetypical G-quadruplex fold needs to be stabilized by metal-cations, which is usually a potassium ion. Here, we show that a noncovalent PEGylation process enabled by electrostatic interactions allows the first metal-free G-quadruplexes in organic solvents. Strikingly, incorporation of an iron-containing porphyrin renders the self-assembled metal-free G-quadruplex catalytically active in organic solvents. Hence, these “supraG4zymes” enable DNA-based catalysis in organic media. The results will allow the broad utilization of DNA G-quadruplexes in nonaqueous environments.

A partir de la pandemia causada por el virus COVID-19, el profesorado en México ha migrado los contenidos de sus cursos a plataformas digitales educativas. Este es el caso en la Escuela de Lenguas Campus Tapachula de la UNACH, donde los docentes han recurrido a nuevas estrategias tecnopedagógicas para ayudar a mejorar la pronunciación en inglés del estudiantado de la Licenciatura en la Enseñanza del Inglés en la modalidad a distancia. Este artículo presenta un análisis del progreso en la pronunciación de inglés del estudiantado después de haber participado en un proyecto colaborativo para generar productos audiovisuales mediadas por las TIC. Este estudio está basado en la investigación-acción, llevado a cabo en dos etapas: la recolección de información necesaria para el diseño instruccional del proyecto colaborativo y la implementación del mismo en donde el estudiantado generó productos audiovisuales digitales para mejorar su pronunciación del inglés. Una vez completado, se recolectaron las opiniones del estudiantado sobre la experiencia de aprendizaje y se observó su progreso en la pronunciación de inglés. El estudiantado confirma que el trabajo colaborativo para realizar los productos audiovisuales, usando herramientas tecnológicas tanto nuevas como conocidas, les ayudó a practicar la pronunciación del inglés durante la pandemia.

Multiple mode resonance shifts in tilted fiber Bragg gratings (TFBGs) are used to simultaneously measure the thickness and the refractive index of TiO2 thin films formed by Atomic Layer Deposition (ALD) on optical fibers. This is achieved by comparing the experimental wavelength shifts of 8 TFBG resonances during the deposition process with simulated shifts from a range of thicknesses (T) and values of the real part of the refractive index (n). The minimization of an error function computed for each (n, T) pair then provides a solution for the thickness and refractive index of the deposited film and, a posteriori, to verify the deposition rate throughout the process from the time evolution of the wavelength shift data. Validations of the results were carried out with a conventional ellipsometer on flat witness samples deposited simultaneously with the fiber and with scanning electron measurements on cut pieces of the fiber itself. The final values obtained by the TFBG (n = 2.25, final thickness of 185 nm) were both within 4% of the validation measurements. This approach provides a method to measure the formation of nanoscale dielectric coatings on fibers in situ for applications that require precise thicknesses and refractive indices, such as the optical fiber sensor field. Furthermore, the TFBG can also be used as a process monitor for deposition on other substrates for deposition methods that produce uniform coatings on dissimilar shaped substrates, such as ALD.

Fundamento: la seropositividad al virus de inmunodeficiencia humana representa en la actualidad un serio problema de salud, debido a su alcance y trascendencia mundial. En Cuba las capitales provinciales registran mayores tasas de incidencia con respecto al resto de los municipios.Objetivo: caracterizar epidemiológicamente los casos seropositivos al virus de inmunodeficiencia humana.Métodos: se realizó un estudio descriptivo y retrospectivo, en el municipio de Cienfuegos, en el periodo comprendido entre 2017 al 2021. El universo estuvo constituido por 134 pacientes. Las variables analizadas fueron: edad, sexo, nivel de escolaridad, orientación sexual, áreas de salud y grupo de pesquisa. Para el análisis de la información, se utilizaron medidas de resumen para variables cuantitativas (porcentajes y tasas).Resultados: las áreas de salud III y VI fueron las de mayores tasas. Predominó el grupo etario de 25-34 años, y el sexo masculino representó el 79,9 % del total. Según la orientación sexual, los homosexuales ocuparon el 58,2 %, y el 32,1 % pertenecieron al grupo de pesquisa captados.Conclusiones: los casos seropositivos al virus de inmunodeficiencia humana descendieron de manera significativa en el último quinquenio, donde los pacientes en edad de la adultez joven fueron los más afectados, así como los hombres que tienen sexo con otros hombres.

This study explores the potential of using a Siamese Network as a biomarker for assessing the effectiveness of Dolphin-Assisted Therapy (DAT) in children with Spastic Cerebral Palsy (SCP). The problem statement revolves around the need for objective measures to evaluate the impact of DAT on patients with SCP, considering the subjective nature of traditional assessment methods. The methodology involves training a Siamese network, a type of neural network designed to compare similarities between inputs, using data collected from SCP patients undergoing DAT sessions. The study employed Event-Related Potential (ERP) and Fast Fourier Transform (FFT) analyses to examine cerebral activity and brain rhythms, proposing the use of SNN to compare electroencephalographic (EEG) signals of children with cerebral palsy before and after Dolphin-Assisted Therapy. Testing on samples from four children yielded a high average similarity index of 0.9150, indicating consistent similarity metrics before and after therapy. The network is trained to learn patterns and similarities between pre- and post-therapy evaluations, in order to identify biomarkers indicative of therapy effectiveness. Notably, the Siamese Network’s architecture ensures that comparisons are made within the same feature space, allowing for more accurate assessments. The results of the study demonstrate promising findings, indicating different patterns in the output of the Siamese Network that correlate with improvements in symptoms of SCP post-DAT. Confirming these observations will require large, longitudinal studies but such findings would suggest that the Siamese Network could have utility as a biomarker in monitoring treatment responses for children with SCP who undergo DAT and offer them more objective as well as quantifiable manners of assessing therapeutic interventions. Great discrepancies in neuronal voltage perturbations, 7.9825 dB on average at the specific samples compared to the whole dataset (6.2838 dB), imply a noted deviation from resting activity. These findings indicate that Dolphin-Assisted Therapy activates particular brain regions specifically during the intervention.

Introducción: La violencia en contra de la mujer es un problema que afecta a la población mundial, teniendo su máxima expresión a través del feminicidio. Debido a la reciente y desigual legislación de este fenómeno, estudios al respecto son recientes y han girado en torno a determinar tipologías de agresores donde la criminalidad juega un papel importante como factor de riesgo. Así mismo, existen muy pocos estudios directos con personas que han cometido feminicidio. Objetivo: Conocer el nivel de criminalidad en sentenciados por el delito de feminicidio. Materiales y métodos: A través de una lista con 20 dimensiones se evaluó a 62 personas privadas de su libertad por el delito de feminicidio. Resultados: Se encontraron cuatro niveles de criminalidad que van de baja a muy alta, los principales indicadores que marcan la diferencia entre estos niveles son los que se refieren a la violencia de pareja e historia de consumo de alcohol y drogas. Conclusión: Los indicadores que marcan la diferencia entre los niveles de criminalidad, se encuentran una historia de violencia hacia la pareja como una forma de resolver conflictos, asociada al consumo de alcohol y sustancias psicoactivas.

BackgroundSystemic arterial hypertension is linked to a heightened risk of cardiovascular diseases on a global scale. In Mexico, nearly half of adults in vulnerable conditions experience hypertension. Imbalance in the oral and intestinal microbiota composition has been observed in patients with hypertension, documented by a decrease of bacteria producing short-chain fatty acids, which play a critical role in blood pressure regulation.AimTo examine the cytokines’ profile and assess the characteristics of oral and gut microbiota in obesity-related hypertension in Mexican patients.MethodsA cross-sectional, observational, and analytical study was carried out. Twenty-two patients were categorized by their body mass index (BMI) as overweight and obese, and the diagnosis of primary hypertension. DNA from supragingival dental plaque and feces samples was used to carry out 16S rRNA sequencing. Additionally, 13 cytokines were quantified.ResultsIn the oral microbiota, Kluyvera was found to be significantly enriched in obese compared to overweight patients. Instead, the gut microbiota was dominated by Firmicutes. However, the correlation between certain genera and proinflammatory cytokines was noted.ConclusionThis exploratory study provides insights into the complex relationship between the oral and gut microbiota and their association with systemic inflammation in obesity-related hypertension.