Tensiones entre el acceso a la justicia y personas con padecimiento en salud mental

En el presente trabajo buscamos analizar un recorte institucional que visibiliza la afectación de derechos de sujetos en situación de vulnerabilidad. Describiremos cómo opera o incide la intervención desde el ámbito institucional en el que se realizó la práctica, en pos de propiciar los derechos de las personas. Desarrollaremos cómo los marcos legales (Ley de Protección integral de derechos de NNyA; Ley de Salud Mental, nuevo Código Civil y Comercial de la Argentina y la Convención sobre los Derechos del Niño) afectan la intervención.In the present work we seek to analyze an institutional cut that makes visible the affectation of rights of subjects in vulnerable situations. We will describe how the intervention operates or affects from the institutional sphere in which the practice was carried out, in order to promote people’s rights. We will develop how the legal frameworks (Law for the Comprehensive Protection of the Rights of NNyA; Mental Health Law, new Civil and Commercial Code and the Convention on the Rights of the Child) affect the intervention.Facultad de Psicologí

Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia.

N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex3,4. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown5-7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3-METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy

The profile and dynamics of RNA modifications in animals

More than a hundred distinct modified nucleosides have been identified in RNA, but little is known about their distribution across different organisms, dynamic nature and their response to cellular and environmental stress. Mass spectrometry based methods have been at the forefront of identifying and quantifying modified nucleosides. However, they often require synthetic reference standards, which do not exist for many modified nucleosides and therefore impedes their analysis. Here, we use a metabolic labeling approach to rapidly generate bio-isotopologues of the complete C. elegans transcriptome and its modifications, and use them as reference standards to characterize the RNA modification profile in this multicellular organism via an untargeted liquid-chromatography tandem high-resolution mass spectrometry (LC-MS/HRMS) approach. We furthermore show that several of these RNA modifications have a dynamic response to environmental stress and that in particular changes in the tRNA wobble base modification 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) lead to codon biased gene expression changes in starved animals.CRUK Wellcome Trus

FTO influences adipogenesis by regulating mitotic clonal expansion

The fat mass and obesity-associated (FTO) gene plays a pivotal role in regulating body weight and fat mass; however, the underlying mechanisms are poorly understood. Here we show that primary adipocytes and mouse embryonic fibroblasts (MEFs) derived from FTO overexpression (FTO-4) mice exhibit increased potential for adipogenic differentiation, while MEFs derived from FTO knockout (FTO-KO) mice show reduced adipogenesis. As predicted from these findings, fat pads from FTO-4 mice fed a high-fat diet show more numerous adipocytes. FTO influences adipogenesis by regulating events early in adipogenesis, during the process of mitotic clonal expansion. The effect of FTO on adipogenesis appears to be mediated via enhanced expression of the pro-adipogenic short isoform of RUNX1T1, which enhanced adipocyte proliferation, and is increased in FTO-4 MEFs and reduced in FTO-KO MEFs. Our findings provide novel mechanistic insight into how upregulation of FTO leads to obesity

Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site, and this is required for recruitment of METTL3 to chromatin. Promoter-bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia

Canonical A-to-I and C-to-U RNA Editing Is Enriched at 3′UTRs and microRNA Target Sites in Multiple Mouse Tissues

RNA editing is a process that modifies RNA nucleotides and changes the efficiency and fidelity of the central dogma. Enzymes that catalyze RNA editing are required for life, and defects in RNA editing are associated with many diseases. Recent advances in sequencing have enabled the genome-wide identification of RNA editing sites in mammalian transcriptomes. Here, we demonstrate that canonical RNA editing (A-to-I and C-to-U) occurs in liver, white adipose, and bone tissues of the laboratory mouse, and we show that apparent non-canonical editing (all other possible base substitutions) is an artifact of current high-throughput sequencing technology. Further, we report that high-confidence canonical RNA editing sites can cause non-synonymous amino acid changes and are significantly enriched in 3′ UTRs, specifically at microRNA target sites, suggesting both regulatory and functional consequences for RNA editing