Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates

Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs(1,2). In reprogramming, the same factors are often used to reprogram many different donor cell types3. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors(4,5), it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l)(6) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.Non peer reviewe

Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic

Effect of recent artisanal small-scale gold mining on the contamination of surface river sediment: Case of Gambia River, Kedougou region, southeastern Senegal

Abstract We report here the first inventory of mercury (Hg) contamination in the region of Kedougou, Senegal, where mercury (Hg) is used for gold amalgamation in artisanal small-scale gold mining (ASGM) activities. Sediment cores were sampled during the dry and wet seasons, and at different locations along the Gambia River in the Kedougou region to evaluate the spatio-temporal trends of Hg distribution related to ASGM activities. The sediment samples were analysed for total mercury and trace element concentrations (Cr, Cu, Zn, Pb, As, and Sc). The results highlight high concentrations of total Hg (reaching up to 9.9 mg kg− 1) in sediment cores sampled in the vicinity of ASGM operations, with the highest values reported for the dry season. The calculation of the Hg Enrichment Factor (EF) using Sc as refractory element confirms high enrichments around active sites of gold mining being proportional to the density of miners and the duration of mining activities. The Hg spatial distribution reveals a very local contamination and a limited downstream dispersion of the contaminant. The high Hg concentrations obtained at ASGM sites largely exceed the Sediment Quality Guidelines (SQGs) and the Probable effect concentration (PEC) for the Protection of Aquatic Life recommendation. Our results demonstrate that the ASGM activities discharged large amounts of Hg into the Gambia River ecosystem and that the accumulation of Hg in sediments may represent a significant human health risk and a potential source of toxicity for aquatic organisms

Effect of recent artisanal small-scale gold mining on the contamination of surface river sediment : case of Gambia River, Kedougou region, southeastern Senegal

We report here the first inventory of mercury (Hg) contamination in the region of Kedougou, Senegal, where mercury (Hg) is used for gold amalgamation in artisanal small-scale gold mining (ASGM) activities. Sediment cores were sampled during the dry and wet seasons, and at different locations along the Gambia River in the Kedougou region to evaluate the spatio-temporal trends of Hg distribution related to ASGM activities. The sediment samples were analysed for total mercury and trace element concentrations (Cr, Cu, Zn, Pb, As, and Sc). The results highlight high concentrations of total Hg (reaching up to 9.9 mg kg(-1)) in sediment cores sampled in the vicinity of ASGM operations, with the highest values reported for the dry season. The calculation of the Hg Enrichment Factor (EF) using Sc as refractory element confirms high enrichments around active sites of gold mining being proportional to the density of miners and the duration of mining activities. The Hg spatial distribution reveals a very local contamination and a limited downstream dispersion of the contaminant. The high Hg concentrations obtained at ASGM sites largely exceed the Sediment Quality Guidelines (SQGs) and the Probable effect concentration (PEC) for the Protection of Aquatic Life recommendation. Our results demonstrate that the ASGM activities discharged large amounts of Hg into the Gambia River ecosystem and that the accumulation of Hg in sediments may represent a significant human health risk and a potential source of toxicity for aquatic organisms

Effect of recent artisanal small-scale gold mining on the contamination of surface river sediment: Case of Gambia River, Kedougou region, southeastern Senegal

We report here the first inventory of mercury (Hg) contamination in the region of Kedougou, Senegal, where mercury (Hg) is used for gold amalgamation in artisanal small-scale gold mining (ASGM) activities. Sediment cores were sampled during the dry and wet seasons, and at different locations along the Gambia River in the Kedougou region to evaluate the spatio-temporal trends of Hg distribution related to ASGM activities. The sediment samples were analyzed for total mercury and trace element concentrations (Cr, Cu, Zn, Pb, As, and Sc). The results highlight high concentrations of total Hg (reaching up to 9.9 mg.kg-1) in sediment cores sampled in the vicinity of ASGM operations, with the highest values reported for the dry season. The calculation of the Hg Enrichment Factor (EF) using Sc as refractory element, confirm high enrichments around active sites of gold mining being proportional to the density of miners and the duration of mining activities. The Hg spatial distribution reveals a very local contamination and a limited downstream dispersion of the contaminant. The high Hg concentrations obtained at ASGM sites largely exceed the Sediment Quality Guidelines (SQGs) and the Probable effect concentration (PEC) for the Protection of Aquatic Life recommendation. Our results demonstrate that the ASGM activities discharged large amounts of Hg into the Gambia River ecosystem and that the accumulation of Hg in sediments may represent a significant human health risk and a potential source of toxicity for aquatic organisms

Generation of Induced Neuronal Cells by the Single Reprogramming Factor ASCL1

Direct conversion of nonneural cells to functional neurons holds great promise for neurological disease modeling and regenerative medicine. We previously reported rapid reprogramming of mouse embryonic fibroblasts (MEFs) into mature induced neuronal (iN) cells by forced expression of three transcription factors: ASCL1, MYT1L, and BRN2. Here, we show that ASCL1 alone is sufficient to generate functional iN cells from mouse and human fibroblasts and embryonic stem cells, indicating that ASCL1 is the key driver of iN cell reprogramming in different cell contexts and that the role of MYT1L and BRN2 is primarily to enhance the neuronal maturation process. ASCL1-induced single-factor neurons (1F-iN) expressed mature neuronal markers, exhibited typical passive and active intrinsic membrane properties, and formed functional pre- and postsynaptic structures. Surprisingly, ASCL1-induced iN cells were predominantly excitatory, demonstrating that ASCL1 is permissive but alone not deterministic for the inhibitory neuronal lineage