Structural determinants of the neuronal glycine transporter 2 for the selective inhibitors ALX1393 and ORG25543

The neuronal glycine transporter GlyT2 modulates inhibitory glycinergic neurotransmission by controlling the extracellular concentration of synaptic glycine and the supply of neurotransmitter to the presynaptic terminal. Spinal cord glycinergic neurons present in the dorsal horn diminish their activity in pathological pain conditions and behave as gate keepers of the touch-pain circuitry. The pharmacological blockade of GlyT2 reduces the progression of the painful signal to rostral areas of the central nervous system by increasing glycine extracellular levels, so it has analgesic action. O-[(2-benzyloxyphenyl-3-fluorophenyl)methyl]-L-serine (ALX1393) and N-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-(phenylmethoxy)benzamide (ORG25543) are two selective GlyT2 inhibitors with nanomolar affinity for the transporter and analgesic effects in pain animal models, although with deficiencies which preclude further clinical development. In this report, we performed a comparative ligand docking of ALX1393 and ORG25543 on a validated GlyT2 structural model including all ligand sites constructed by homology with the crystallized dopamine transporter from Drosophila melanogaster. Molecular dynamics simulations and energy analysis of the complex and functional analysis of a series of point mutants permitted to determine the structural determinants of ALX1393 and ORG25543 discrimination by GlyT2. The ligands establish simultaneous contacts with residues present in transmembrane domains 1, 3, 6, and 8 and block the transporter in outward-facing conformation and hence inhibit glycine transport. In addition, differential interactions of ALX1393 with the cation bound at Na1 site and ORG25543 with TM10 define the differential sites of the inhibitors and explain some of their individual features. Structural information about the interactions with GlyT2 may provide useful tools for new drug discoveryThis work was supported by grants of the Spanish ‘Ministerio de Economía y Competitividad’, grant number SAF2017-84235-R (AEI/FEDER, EU) to B.L.-C. and by institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMS

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Structural Determinants of the Neuronal Glycine Transporter 2 for the Selective Inhibitors ALX1393 and ORG25543

The neuronal glycine transporter GlyT2 modulates inhibitory glycinergic neurotransmission by controlling the extracellular concentration of synaptic glycine and the supply of neurotransmitter to the presynaptic terminal. Spinal cord glycinergic neurons present in the dorsal horn diminish their activity in pathological pain conditions and behave as gate keepers of the touch-pain circuitry. The pharmacological blockade of GlyT2 reduces the progression of the painful signal to rostral areas of the central nervous system by increasing glycine extracellular levels, so it has analgesic action. O-[(2-benzyloxyphenyl-3-fluorophenyl)methyl]-l-serine (ALX1393) and N-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-(phenylmethoxy)benzamide (ORG25543) are two selective GlyT2 inhibitors with nanomolar affinity for the transporter and analgesic effects in pain animal models, although with deficiencies which preclude further clinical development. In this report, we performed a comparative ligand docking of ALX1393 and ORG25543 on a validated GlyT2 structural model including all ligand sites constructed by homology with the crystallized dopamine transporter from Drosophila melanogaster. Molecular dynamics simulations and energy analysis of the complex and functional analysis of a series of point mutants permitted to determine the structural determinants of ALX1393 and ORG25543 discrimination by GlyT2. The ligands establish simultaneous contacts with residues present in transmembrane domains 1, 3, 6, and 8 and block the transporter in outward-facing conformation and hence inhibit glycine transport. In addition, differential interactions of ALX1393 with the cation bound at Na1 site and ORG25543 with TM10 define the differential sites of the inhibitors and explain some of their individual features. Structural information about the interactions with GlyT2 may provide useful tools for new drug discovery. © 2021 American Chemical Society.Ministerio de Economía y Competitividad (España)Fundación Ramón ArecesBanco SantaderDepto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEpu

ODD 17. ApS les histoires de vie comme technique d’apprentissage social et éducatif

El proyecto ODS17 ApS "Historia de Vica como técnica de aprendizaje social y educativo" busca analizar la introducción de una metodología pedagógica, la técnica de “historias de vida”, en el aprendizaje del estudiantado de Trabajo Social, su transformación y repercusiones, así como dar a conocer los ODS en relación a la temática y las competencias transversales Esta técnica es el sello identificador de una forma de empirismo, que insiste en una aproximación humanista a la realidad social (Pujada, 2002). La técnica de la historia de vida se toma como punto de referencia o hilo conductor desde el que trabajar los contenidos de la asignatura “Intermediación, Inserción y Prospección Laboral”. Ello supone una opción para descubrir una nueva e interesante forma de fijar el conocimiento asociando teoría y práctica, comprometiéndose a la reflexión y teorización, Se trabajan temáticas de análisis social, económico, político o cultural, profundizando en la historia, el género, las migraciones, la sanidad o laboral. Se trata de una forma diferente de construir y reflexionar el conocimiento a partir del conjunto de experiencias de los relatos de las personas mayores, familiares y profesionales, de modo que los/as estudiantes se sientan partícipes de su propio proceso de aprendizaje, siendo una forma de adquirir competencias propias de la asignatura. Desde el curso académico 2023-2024, la temática central de la historia de vida se centra en vida laboral de los abuelos y abuelas del estudiantado, principalmente. En la actualidad, a través de la metodología Aprendizaje Servicio, la propuesta busca salir del aula universitaria, ampliándose y enriqueciéndose.. Así se ha conformado un equipo motor coordinado desde la citada asignatura del Departamento de Trabajo Social y Servicios Sociales de la Facultad de Trabajo Social, Universidad Complutense de Madrid, en el que participan miembros de diversos Institutos de Educación Secundaria: IES Cañada Real de Valmojado (Toledo), Escuela Comarcal Arzobispo Morcillo de Valdemoro ( Madrid), IES La Fortuna de Leganés ( Madrid), IES Gerardo Diego, IES San Juan de la Cruz e IES Camilo José Cela de estos tres últimos pertenecientes a Pozuelo de Alarcón ( Madrid), el departamento de Derecho y Trabajo Social de la Facultad de Ciencias Sociales de la Universidad de Salamanca, En este curso se han sumado Eel IES San Isidro de Azuqueca de Heraneres ( Guadalajara), la asociación Jose Luis en Memoria de Constantina ( Sevilla) así como la Oficina de Atención al Estudiante de la Universidad de Extremadura. Por último, se ha constituido el grupo de trabajo de investigación de Historias de Vida como técnica de aprendizaje social y educativo.Universidad Complutense de MadridDepto. de Trabajo Social y Servicios SocialesFac. de Trabajo SocialTRUEsubmitte