Wnt signalling tunes neurotransmitter release by directly targeting Synaptotagmin-1

The functional assembly of the synaptic release machinery is well understood; however, how signalling factors modulate this process remains unknown. Recent studies suggest that Wnts play a role in presynaptic function. To examine the mechanisms involved, we investigated the interaction of release machinery proteins with Dishevelled-1 (Dvl1), a scaffold protein that determines the cellular locale of Wnt action. Here we show that Dvl1 directly interacts with Synaptotagmin-1 (Syt-1) and indirectly with the SNARE proteins SNAP25 and Syntaxin (Stx-1). Importantly, the interaction of Dvl1 with Syt-1, which is regulated by Wnts, modulates neurotransmitter release. Moreover, presynaptic terminals from Wnt signalling-deficient mice exhibit reduced release probability and are unable to sustain high-frequency release. Consistently, the readily releasable pool size and formation of SNARE complexes are reduced. Our studies demonstrate that Wnt signalling tunes neurotransmitter release and identify Syt-1 as a target for modulation by secreted signalling proteins.Fil: Ciani, Lorenza. University College London; Estados UnidosFil: Marzo, Aude. University College London; Estados UnidosFil: Boyle, Kieran. University College London; Estados UnidosFil: Stamatakou, Eleanna. University College London; Estados UnidosFil: Lopes, Douglas M.. University College London; Estados UnidosFil: Anane, Derek. University College London; Estados UnidosFil: McLeod, Faye. University College London; Estados UnidosFil: Rosso, Silvana Beatriz. University College London; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gibb, Alasdair. University College London; Estados UnidosFil: Salinas, Patricia C.. University College London; Estados Unido

Enfermedades crónicas

Adherencia al tratamiento farmacológico y relación con el control metabólico en pacientes con DM2Aluminio en pacientes con terapia de reemplazo renal crónico con hemodiálisis en Bogotá, ColombiaAmputación de extremidades inferiores: ¿están aumentando las tasas?Consumo de edulcorantes artificiales en jóvenes universitariosCómo crecen niños normales de 2 años que son sobrepeso a los 7 añosDiagnóstico con enfoque territorial de salud cardiovascular en la Región MetropolitanaEfecto a corto plazo de una intervención con ejercicio físico, en niños con sobrepesoEfectos de la cirugía bariátrica en pacientes con síndrome metabólico e IMC < 35 KG/M2Encuesta mundial de tabaquismo en estudiantes de profesiones de saludEnfermedades crónicas no transmisibles: Consecuencias sociales-sanitarias de comunidades rurales en ChileEpidemiología de las muertes hospitalarias por patologías relacionadas a muerte encefálica, Chile 2003-2007Estado nutricional y conductas alimentarias en adolescentes de 4º medio de la Región de CoquimboEstudio de calidad de vida en una muestra del plan piloto para hepatitis CEvaluación del proceso asistencial y de resultados de salud del GES de diabetes mellitus 2Factores de riesgo cardiovascular en población universitaria de la Facsal, universidad de TarapacáImplicancias psicosociales en la génesis, evolución y tratamiento de pacientes con hipertensión arterial esencialInfarto agudo al miocardio (IAM): Realidad en el Hospital de Puerto Natales, 2009-2010Introducción de nuevas TIC y mejoría de la asistencia a un programa de saludNiños obesos atendidos en el Cesfam de Puerto Natales y su entorno familiarPerfil de la mortalidad por cáncer de cuello uterino en Río de JaneiroPerfil del paciente primo-consultante del Programa de Salud Cardiovascular, Consultorio Cordillera Andina, Los AndesPrevalencia de automedicación en mujeres beneficiarias del Hospital Comunitario de Til-TiPrevalencia de caries en población preescolar y su relación con malnutrición por excesoPrevalencia de retinopatía diabética en comunas dependientes del Servicio de Salud Metropolitano Occidente (SSMOC)Problemas de adherencia farmacológica antihipertensiva en población mapuche: Un estudio cualitativoRol biológico de los antioxidantes innatos en pacientes portadores de VIH/SidaSobrepeso en empleados de un restaurante de una universidad pública del estado de São Paul

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

Neuronal development and axon growth are altered by glyphosate through a WNT non-canonical signaling pathway

The growth and morphological differentiation of neurons are critical events in the establishment of proper neuronal connectivity and functioning. The developing nervous system is highly susceptible to damage caused by exposure to environmental contaminants. Glyphosate-containing herbicides are the most used agrochemicals in the world, particularly on genetically modified plants. Previous studies have demonstrated that glyphosate induces neurotoxicity in mammals. Therefore, its action mechanism on the nervous system needs to be determined. In this study, we report about impaired neuronal development caused by glyphosate exposure. Particularly, we observed that the initial axonal differentiation and growth of cultured neurons is affected by glyphosate since most treated cells remained undifferentiated after 1 day in culture. Although they polarized at 2 days in vitro, they elicited shorter and unbranched axons and they also developed less complex dendritic arbors compared to controls. To go further, we attempted to identify the cellular mechanism by which glyphosate affected neuronal morphology. Biochemical approaches revealed that glyphosate led to a decrease in Wnt5a level, a key factor for the initial neurite development and maturation, as well as inducing a down-regulation of CaMKII activity. This data suggests that the morphological defects would likely be a consequence of the decrease in both Wnt5a expression and CaMKII activity induced by glyphosate. Additionally, these changes might be reflected in a subsequent neuronal dysfunction. Therefore, our findings highlight the importance of establishing rigorous control on the use of glyphosate-based herbicides in order to protect mammals' health.Fil: Coullery, Romina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Laboratorio de Toxicología Experimental; ArgentinaFil: Ferrari, María Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Laboratorio de Toxicología Experimental; ArgentinaFil: Rosso, Silvana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Laboratorio de Toxicología Experimental; Argentin

Exposure to glyphosate during pregnancy induces neurobehavioral alterations and downregulation of Wnt5a-CaMKII pathway

Glyphosate-based formulations are the most popular herbicide used around the world. These herbicides are widely applied in agriculture to control weeds on genetically modified crops. Although there is much evidence showing that glyphosate-based herbicides induce toxic effect on reproductive and hepatic systems, and also cause oxidative damage on cells, studies from recent years revealed that the nervous system may represent a key target for their toxicity. In the present work, we evaluated the effect of glyphosate (without adjuvants) in neonate rats after gestational exposure. Particularly, we examined whether glyphosate during gestation affected the nervous system function at early development. Pregnant Wistar rats were treated with 24 or 35 mg/kg of pure glyphosate every 48 h and neurobehavioral studies were performed. Our results indicated that gestational exposure to glyphosate induced changes in reflexes development, motor activity and cognitive function, in a dose-dependent manner. To go further, we evaluated whether prenatal exposure to glyphosate affected the Ca+2-mediated Wnt non-canonical signaling pathway. Results indicated that embryos exposed to glyphosate showed an inhibition of Wnt5a-CaMKII signaling pathway, an essential cascade controlling the formation and integration of neural cir-cuits. Taken together, these findings suggest that gestational exposure to glyphosate leads to a downregulation of Wnt/Ca+2 pathway that could induce a developmental neurotoxicity evidenced by deficits at behavioral and cognitive levels in rat pups.Fil: Coullery, Romina Paola. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias Fisiológicas. Área de Toxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Pacchioni, Alejandra Maria. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias Fisiológicas. Área de Toxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Rosso, Silvana Beatriz. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias Fisiológicas. Área de Toxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentin

Role of Wnt/beta-catenin pathway in the nucleus accumbens in long-term cocaine-induced neuroplasticity : a possible novel target for addiction treatment

Cocaine addiction is a chronic relapsing disorder characterized by the loss of control over drug-seeking and taking, and continued drug use regardless of adverse consequences. Despite years of research, effective treatments for psycho-stimulant addiction have not been identified. Persistent vulnerability to relapse arises from a number of long-lasting adaptations in the reward circuitry that mediate the enduring response to the drug. Recently, we reported that the activity of the canonical or Wnt/β-catenin pathway in the prefrontal cortex (PFC) is very important in the early stages of cocaine-induced neuroadaptations. In the present work, our main goal was to elucidate the relevance of this pathway in cocaine-induced long-term neuroadaptations that may underlie relapse. We found that a cocaine challenge, after a period of abstinence, induced an increase in the activity of the pathway which is revealed as an increase in the total and nuclear levels of β-catenin (final effector of the pathway) in the nucleus accumbens (NAcc), together with a decrease in the activity of glycogen synthase kinase 3β (GSK3β). Moreover, we found that the pharmacological modulation of the activity of the pathway has long-term effects on the cocaine-induced neuroplasticity at behavioral and molecular levels. All the results imply that changes in the Wnt/β-catenin pathway effectors are long-term neuroadaptations necessary for the behavioral response to cocaine. Even though more research is needed, the present results introduce the Wnt canonical pathway as a possible target to manage cocaine long-term neuroadaptations.Fil: Cuesta, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina.Fil: Cuesta, Santiago. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias de los Alimentos y del Medioambiente. Área Toxicología; Argentina.Fil: Batuecas, Jorgelina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias de los Alimentos y del Medioambiente. Área Toxicología; Argentina.Fil: Severin, María Julia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias de los Alimentos y del Medioambiente. Área Toxicología; Argentina.Fil: Funes, Alejandrina. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina.Fil: Funes, Alejandrina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias de los Alimentos y del Medioambiente. Área Toxicología; Argentina.Fil: Rosso, Silvana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina.Fil: Rosso, Silvana Beatriz. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias de los Alimentos y del Medioambiente. Área Toxicología; Argentina.Fil: Pacchioni, Alejandra María. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina.Fil: Pacchioni, Alejandra María. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias de los Alimentos y del Medioambiente. Área Toxicología; Argentina

Wnt/beta-catenin pathway in the prefrontal cortex is required for cocaine-induced neuroadaptations

Behavioral sensitization is a progressive and enduring enhancement of the motor stimulant effects elicited by repeated administration of drugs of abuse. It can be divided into two distinct temporal and anatomical domains, termed initiation and expression, which are characterized by specific molecular and neurochemical changes. This study examines the role of the Wnt canonical pathway mediating the induction of cocaine sensitization. We found that β-catenin levels in the prefrontal cortex (PFC), amygdala (Amyg) and dorsal striatum (CPu) are decreased in animals that show sensitization. Accordingly, GSK3β activity levels are increased in the same areas. Moreover, β-catenin levels in nuclear fraction, mRNA expression of Axin2 and Wnt7b are decreased in the PFC of sensitized animals. Then, in order to demonstrate that changes in the PFC are crucial for initiation of sensitization, we either rescue β-catenin levels with a systemic treatment of a GSK3β inhibitor (Lithium Chloride) or inhibit Wnt/β-catenin pathway with an intracerebral infusion of Sulindac before each cocaine injection. As expected, rescuing β-catenin levels in the PFC as well as CPu and Amyg blocks cocaine-induced sensitization, while decreasing β-catenin levels exclusively in the PFC exacerbates it. Therefore, our results demonstrate a new role for the Wnt/β-catenin pathway as a required neuroadaptation in inducing behavioral sensitization.Fil: Cuesta, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina.Fil: Cuesta, Santiago. Douglas Mental Health University Institute; Canada.Fil: Cuesta, Santiago. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias de los Alimentos y del Medioambiente. Área Toxicología; Argentina.Fil: Severin, María Julia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias de los Alimentos y del Medioambiente. Área Toxicología; Argentina.Fil: Batuecas, Jorgelina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias de los Alimentos y del Medioambiente. Área Toxicología; Argentina.Fil: Rosso, Silvana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina.Fil: Rosso, Silvana Beatriz. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias de los Alimentos y del Medioambiente. Área Toxicología; Argentina.Fil: Pacchioni, Alejandra María. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina.Fil: Pacchioni, Alejandra María. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias de los Alimentos y del Medioambiente. Área Toxicología; Argentina

Wnt/β-catenin pathway in the prefrontal cortex is required for cocaine-induced neuroadaptations

Behavioral sensitization is a progressive and enduring enhancement of the motor stimulant effects elicited by repeated administration of drugs of abuse. It can be divided into two distinct temporal and anatomical domains, termed initiation and expression, which are characterized by specific molecular and neurochemical changes. This study examines the role of the Wnt canonical pathway mediating the induction of cocaine sensitization. We found that β-catenin levels in the prefrontal cortex (PFC), amygdala (Amyg) and dorsal striatum (CPu) are decreased in animals that show sensitization. Accordingly, GSK3β activity levels are increased in the same areas. Moreover, β-catenin levels in nuclear fraction, mRNA expression of Axin2 and Wnt7b are decreased in the PFC of sensitized animals. Then, in order to demonstrate that changes in the PFC are crucial for initiation of sensitization, we either rescue β-catenin levels with a systemic treatment of a GSK3β inhibitor (Lithium Chloride) or inhibit Wnt/β-catenin pathway with an intracerebral infusion of Sulindac before each cocaine injection. As expected, rescuing β-catenin levels in the PFC as well as CPu and Amyg blocks cocaine-induced sensitization, while decreasing β-catenin levels exclusively in the PFC exacerbates it. Therefore, our results demonstrate a new role for the Wnt/β-catenin pathway as a required neuroadaptation in inducing behavioral sensitization.Fil: Cuesta, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Douglas Mental Health University Institute; Canadá. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Severin, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Batuecas, Jorgelina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Rosso, Silvana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Pacchioni, Alejandra Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentin

Glyphosate exposure induces synaptic impairment in hippocampal neurons and cognitive deficits in developing rats

Glyphosate is the active ingredient of several widely used herbicide formulations. Studies based on Glyphosate exposure in diferent experimental models have suggested that the nervous system represented a key target for its toxicity. Previously, we demonstrated that exposure to glyphosate during gestation induces defcits on behavioral and cognitive function in rats. The aim of the present work was to examine whether cognitive dysfunction induced by Glyphosate was connected to changes on synapse formation and maturation. To understand how glyphosate afects synaptic assembly, we performed in vitro assays on cultured hippocampal neurons that were exposed to the herbicide (0.5 or 1 mg/mL) for 5 or 10 days. Biochemical and immunocytochemical approaches revealed that Glyphosate treated neurons showed a decrease on dendritic complexity and synaptic spine formation and maturation. Moreover, results indicated that Glyphosate decreased synapse formation in hippocampal neurons. To evaluate these efects in vivo, pup rats were treated with 35 or 70 mg/kg of Glyphosate from PND 7 to PND 27, every 48 h. Results indicated that Glyphosate postnatal exposure induced cognitive impairments, since recognition and spatial memory were altered. To go further, we evaluated synaptic protein expression and synaptic organization in hippocampus. Images revealed that Glyphosate treatment downregulates synapsin-1, PSD-95, and CaMKII expression, and also decreased PSD-95 clustering in hippocampus. Taken together, these fndings demonstrate for the frst time that Glyphosate exposure afects synaptic assembly and reduced synaptic protein expression in hippocampus and that likely triggers the impairment of cognitive function and neuronal connectivity.Fil: Luna, Sebastian Alberto. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias Fisiológicas. Área de Toxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Neila, Lorena Paola. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias Fisiológicas. Área de Toxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Vena, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas Centro Científico Tecnológico - CONICET -Rosario. Instituto de Biologia Molecular y Celular de Rosario; ArgentinaFil: Borgatello Lozano, Conrado Gabriel. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias Fisiológicas. Área de Toxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Rosso, Silvana Beatriz. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Ciencias Fisiológicas. Área de Toxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentin