Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants

Coordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2−/− lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction. Our data from human embryonic stem cells, when combined with analysis of available foetal cortical gene expression data, de novo rare variants and GWAS statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Early left ventricular abnormalities in children with heterozygous familial hypercholesterolemia

Background. There are few data available on cardiac morphology and function in children with heterozygous familial hypercholesterolemia (FH). Such patients represent a unique clinical model to assess the effect of pure hypercholesterolemia on cardiac morphology and function, excluding the effect of co-morbidities. Speckle tracking echocardiography (STE), a relatively new echo modality, allows to assess myocardial deformation properties. Aim. We sought to define in FH children the preclinical effects of isolated hypercholesterolemia on the cardiovascular system by examining left ventricular (LV) function using STE. Methods. We prospectively studied 90 children (45 FH children and 45 controls, mean age 11±3 years). Results. FH children showed thicker LV walls and significantly higher LV mass indexed for height 2.7 (p=0.0008) and for body surface area (p<0.0001). LV ejection fraction was similar for both groups. Assessment of diastolic function demonstrated a longer deceleration time(p<0.0001), a reduced early diastolic mitral annular velocity (p<0.0001), and higher transmitral early\ early diastolic mitral annular velocity ratio (p=0.0003) in FH children. Longitudinal and circumferential myocardial deformation of the LV were significantly reduced (p<0.0001) whereas radial deformation was increased in FH children (p=0.04) compared to controls. Conclusions. This study demonstrates that hypercholesterolemia is associated with significant LV morphological and functional alterations during childhood. Our findings also suggest that reduction in longitudinal and circumferential deformations is compensated by an increasing radial strain in FH children with normal LV ejection fraction. This study raises the questions of the clinical importance of these findings, and the opportunity for cholesterol lowering therapy. The potential benefits and risks of such treatment at young age need to be addressed in larger and long term studies

Roles of the N and C terminal domains of the interleukin-3 receptor alpha chain in receptor function.

Copyright © 1997 by The American Society of HematologyThe interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and IL-5 receptor alpha chains are each composed of three extracellular domains, a transmembrane domain and a short intracellular region. Domains 2 and 3 constitute the cytokine receptor module (CRM), typical of the cytokine receptor superfamily; however, the function of the N-terminal domain is not known. We have investigated the functions of the N-terminal and C-terminal domains of the IL-3 receptor (IL-3R) alpha chain. We find that cells transfected with the receptor beta chain (h beta c) and a truncated IL-3R alpha that is devoid of the intracellular region fail to proliferate or to activate STAT5 in response to human IL-3, despite binding the IL-3 with affinity indistinguishable from that of full-length receptor. In addition, IL-3-induced phosphorylation of h beta c was not detected. Thus, the IL-3R alpha intracellular region does not contribute detectably to stabilization of the receptor/ligand complex, but is essential for signal propagation. In contrast, a truncated IL-3R alpha with the N-terminal domain deleted interacts functionally with the beta chain; mouse cells transfected with these receptor chains proliferate in response to human IL-3 and STAT5 transcription factor is activated. High- and low-affinity binding sites are retained, although the affinity for IL-3 is decreased 15-fold, indicating a significant role for the N-terminal domain in IL-3 binding.S.C. Barry, E. Korpelainen, Q. Sun, F.C. Stomski, P.A.B. Moretti, H. Wakao, R.J. D’Andrea, M.A. Vadas, A.F. Lopez, and G.J. Goodal

Atividade de urease no solo com feijoeiro influenciada pela cobertura vegetal e sistemas de plantio

A urease é a enzima que catalisa a hidrólise da ureia em dióxido de carbono e amônia. A distribuição da urease e os fatores que a influenciam têm importância relevante em vista do uso da ureia na agricultura. Nesse sentido, este estudo teve como objetivo definir a época adequada de coleta de solo, após adubação nitrogenada no feijoeiro comum, para medir a atividade de urease e seu perfil, considerando os efeitos residuais de diferentes plantas de cobertura e de sistema de preparo do solo. O experimento foi instalado em um Latossolo Vermelho distrófico e o feijoeiro, cultivar BRS Valente, semeado em junho de 2005, em sucessão a quatro plantas de cobertura de solo: capim-mombaça, milho em consórcio com braquiária, sorgo granífero e estilosantes, e dois sistemas de cultivo, direto e convencional. O delineamento experimental foi o de blocos ao acaso em parcelas divididas. As amostras de solo foram coletadas aos 3, 6, 8, 10 e 12 dias após a aplicação da ureia em cobertura no feijoeiro. A maior atividade de urease no solo ocorreu quando o feijoeiro foi cultivado após capim-mombaça, independentemente do preparo do solo e da época de sua avaliação. A mobilização do solo em cultivo no sistema plantio direto determinou menor atividade de urease, independentemente das espécies de cobertura e das épocas de sua avaliação. O pico de atividade de urease ocorreu entre o sétimo e o oitavo dia após a aplicação de ureia, independentemente das espécies de cobertura e do preparo do solo sob cultivo irrigado do feijoeiro comum

Frações de carbono em topossequências de solos sob eucalipto com diferentes históricos de uso

No Brasil, boa parte dos plantios florestais tem sido realizada em solos que apresentam algum grau de degradação física, química ou biológica. A proteção ao solo fornecida pelas árvores, em função da deposição de serapilheira, constitui um dos processos de recuperação de áreas degradadas, e, como a matéria orgânica está relacionada com muitos dos atributos físicos, químicos e biológicos do solo, ela se caracteriza como um fator-chave na manutenção da qualidade ambiental de sistemas florestais. Assim, objetivou-se neste trabalho caracterizar frações da matéria orgânica em solos sob cultivo mínimo de eucalipto com diferentes históricos de uso e posições na paisagem. O estudo foi realizado em três hortos florestais (HFs): Terra Dura, Canafístula e Sanga das Pedras, cultivados com eucalipto no Estado do Rio Grande do Sul. Os solos foram amostrados nas profundidades de 0-5, 5-20 e 20-40 cm. Na profundidade de 0-5 cm, a maioria dos Argissolos dos HFs estudados apresentou teores de carbono orgânico (CO) superiores aos de matas nativas adjacentes. Nas áreas cultivadas, há maior armazenamento de CO no HF Canafístula, sendo notados, em geral, menores teores de CO no terço inferior da encosta em relação às outras posições das topossequências avaliadas. O índice de humificação, em geral, é maior nas áreas de mata em comparação às áreas cultivadas; contudo, ele varia em função da profundidade do solo, da posição amostrada na topossequência e do HF avaliado. Nas profundidades de 0-5 e 5-20 cm, a abundância natural de 13C dos HFs é similar à das áreas de mata nativa, porém há maior teor de 13C na camada mais profunda dos solos cultivados, o que sinaliza para a contribuição à matéria orgânica do solo (MOS) de C oriundo das pastagens que antecederam o eucalipto