Bisphosphoglycerate mutase deficiency protects against cerebral malaria and severe malaria-induced anemia

The replication cycle and pathogenesis of the Plasmodium malarial parasite involves rapid expansion in red blood cells (RBCs), and variants of certain RBC-specific proteins protect against malaria in humans. In RBCs, bisphosphoglycerate mutase (BPGM) acts as a key allosteric regulator of hemoglobin/oxyhemoglobin. We demonstrate here that a loss-of-function mutation in the murine Bpgm (BpgmL166P) gene confers protection against both Plasmodium-induced cerebral malaria and blood-stage malaria. The malaria protection seen in BpgmL166P mutant mice is associated with reduced blood parasitemia levels, milder clinical symptoms, and increased survival. The protective effect of BpgmL166P involves a dual mechanism that enhances the host’s stress erythroid response to Plasmodium-driven RBC loss and simultaneously alters the intracellular milieu of the RBCs, including increased oxyhemoglobin and reduced energy metabolism, reducing Plasmodium maturation, and replication. Overall, our study highlights the importance of BPGM as a regulator of hemoglobin/oxyhemoglobin in malaria pathogenesis and suggests a new potential malaria therapeutic target

Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression

Breast cancer progression is characterized by changes in cellular metabolism that contribute to enhanced tumour growth and adaptation to microenvironmental stresses. Metabolic changes within breast tumours are still poorly understood and are not as yet exploited for therapeutic intervention, in part due to a high level of metabolic heterogeneity within tumours. The metabolic profiles of breast cancer cells are flexible, providing dynamic switches in metabolic states to accommodate nutrient and energy demands and further aggravating the challenges of targeting metabolic dependencies in cancer. In this review, we discuss the intrinsic and extrinsic factors that contribute to metabolic heterogeneity of breast tumours. Next, we examine how metabolic flexibility, which contributes to the metabolic heterogeneity of breast tumours, can alter epigenetic landscapes and increase a variety of pro-tumorigenic functions. Finally, we highlight the difficulties in pharmacologically targeting the metabolic adaptations of breast tumours and provide an overview of possible strategies to sensitize heterogeneous breast tumours to the targeting of metabolic vulnerabilities

L’étude de la réussite scolaire au Québec : une analyse historicoculturelle de l’activité d’un centre de recherche, le CRIRES

Le concept de réussite scolaire est examiné à travers les définitions, les axes de recherche et les moyens d’agir qu’ont retenus les chercheurs du Centre de recherche et d’intervention sur la réussite scolaire (CRIRES) depuis sa création en 1992. La théorie historicoculturelle est appliquée à ce cas et le modèle d’Engeström (1987, 1999) sert de cadre de référence pour l’analyse du système éducatif québécois en tant que système d’activité qui a pour finalité la réussite scolaire des élèves. Cette analyse, de niveau méta, examine l’activité des agents de la réussite scolaire, notamment les outils et instruments d’intervention mis en oeuvre dans différents contextes ainsi que certains rôles, normes et politiques qui en sont ressortis. L’analyse se veut proactive et met en lumière les modes d’intervention, en milieu scolaire et postsecondaire, des agents de la réussite scolaire au sein de leur communauté (classe, école, communauté locale ou élargie). Elle fait ressortir les éléments suivants : 1) la définition donnée en 1992 de la réussite scolaire, à savoir l’atteinte d’objectifs d’apprentissage propres à chaque étape des cheminements scolaires, est un artefact culturel utile malgré certaines réserves que les chercheurs du CRIRES expriment périodiquement à son sujet; 2) les axes de recherche orientent la médiation de l’innovation en privilégiant une grande variété d’outils et d’instruments ainsi que l’examen de leurs retombées dans des contextes précis; 3) le CRIRES conçoit de façon de plus en plus explicite son champ de recherche d’un point de vue systémique. Abstract The concept of school success is examined through the definitions, research axes and actions chosen by researchers from Centre de recherche et d’intervention sur la réussite scolaire (CRIRES) since its creation in 1992. The historical-cultural theory is applied to this case, and the Engeström model (1987, 1999) is used as a frame of reference to analyze the Québec education system whose goal is success for the students. At the meta level, this analysis examines school success agents, such as intervention tools used in different contexts, as well as certain roles, standards and policies that go along with them. The analysis is proactive and shows intervention modes in the school and post-secondary milieus, agents of school success within the community (class, school, local community or society). What emerges is that 1) the 1992 definition for school success, to reach the learning objectives for each level, is a cultural artifact despite certain reserves that the CRIRES researchers periodically express on this subject, 2) the research axes orient the mediation of innovation by using a wide variety of instruments and the examination of their results in specific contexts, and 3) CRIRES is developing, in a more and more explicit way, its scope of research from a systemic point of view. Resumen El concepto de éxito escolar se examina a través de las definiciones, los ejes de investigación y los medios de intervención que han sido validados por los investigadores del Centro de investigaciones y de intervención sobre el éxito escolar (CRIRES) desde su creación en 1992. Se aplica la teoría histórico-cultural a este caso y el modelo de Engeström (1987, 1999) sirve de marco de referencia para el análisis del sistema educativo quebequense en tanto que sistema de actividad cuya finalidad es el éxito escolar de los alumnos. Este análisis, de nivel meta, examina la actividad de los agentes del éxito escolar, entre otros, las herramientas de intervención propuestas en diferentes contextos así como ciertos roles, normas y políticas que han resultado. El análisis es proactivo e ilumina los modos de intervención, en medio escolar y post-secundario, los agentes del éxito escolar en el seno de sus comunidades (clase, escuela, comunidad local y ampliada). Sobresale que: 1) la definición dada en 1002 del éxito escolar, es decir, el logro de objetivos de aprendizaje propios a cada etapa de las progresiones escolares, es un artefacto cultural útil a pesar de algunas reservas que los investigadores del CRIRES expresan periódicamente sobre dicho sujeto; 2) los ejes de investigación orientan la mediación de la innovación privilegiando una gran variedad de instrumentos así como el examen de sus repercusiones en contextos precisos y 3) el CRIRES concibe de manera cada vez más explicita su campo de investigación desde un punto de vista sistémico

Genome-wide computational prediction of transcriptional regulatory modules reveals new insights into human gene expression

The identification of regulatory regions is one of the most important and challenging problems toward the functional annotation of the human genome. In higher eukaryotes, transcription-factor (TF) binding sites are often organized in clusters called cis-regulatory modules (CRM). While the prediction of individual TF-binding sites is a notoriously difficult problem, CRM prediction has proven to be somewhat more reliable. Starting from a set of predicted binding sites for more than 200 TF families documented in Transfac, we describe an algorithm relying on the principle that CRMs generally contain several phylogenetically conserved binding sites for a few different TFs. The method allows the prediction of more than 118,000 CRMs within the human genome. A subset of these is shown to be bound in vivo by TFs using ChIP-chip. Their analysis reveals, among other things, that CRM density varies widely across the genome, with CRM-rich regions often being located near genes encoding transcription factors involved in development. Predicted CRMs show a surprising enrichment near the 3′ end of genes and in regions far from genes. We document the tendency for certain TFs to bind modules located in specific regions with respect to their target genes and identify TFs likely to be involved in tissue-specific regulation. The set of predicted CRMs, which is made available as a public database called PReMod (http://genomequebec.mcgill.ca/PReMod), will help analyze regulatory mechanisms in specific biological systems

PGC-1α supports glutamine metabolism in breast cancer

Background: Glutamine metabolism is a central metabolic pathway in cancer. Recently, reductive carboxylation of glutamine for lipogenesis has been shown to constitute a key anabolic route in cancer cells. However, little is known regarding central regulators of the various glutamine metabolic pathways in cancer cells. Methods: The impact of PGC-1α and ERRα on glutamine enzyme expression was assessed in ERBB2+ breast cancer cell lines with quantitative RT-PCR, chromatin immunoprecipitation, and immunoblotting experiments. Glutamine flux was quantified using 13C-labeled glutamine and GC/MS analyses. Functional assays for lipogenesis were performed using 14C-labeled glutamine. The expression of glutamine metabolism genes in breast cancer patients was determined by bioinformatics analyses using The Cancer Genome Atlas. Results: We show that the transcriptional coactivator PGC-1α, along with the transcription factor ERRα, is a positive regulator of the expression of glutamine metabolism genes in ERBB2+ breast cancer. Indeed, ERBB2+ breast cancer cells with increased expression of PGC-1α display elevated expression of glutamine metabolism genes. Furthermore, ERBB2+ breast cancer cells with reduced expression of PGC-1α or when treated with C29, a pharmacological inhibitor of ERRα, exhibit diminished expression of glutamine metabolism genes. The biological relevance of the control of glutamine metabolism genes by the PGC-1α/ERRα axis is demonstrated by consequent regulation of glutamine flux through the citric acid cycle. PGC-1α and ERRα regulate both the canonical citric acid cycle (forward) and the reductive carboxylation (reverse) fluxes; the latter can be used to support de novo lipogenesis reactions, most notably in hypoxic conditions. Importantly, murine and human ERBB2+ cells lines display a significant dependence on glutamine availability for their growth. Finally, we show that PGC-1α expression is positively correlated with that of the glutamine pathway in ERBB2+ breast cancer patients, and high expression of this pathway is associated with reduced patient survival. Conclusions: These data reveal that the PGC-1α/ERRα axis is a central regulator of glutamine metabolism in ERBB2+ breast cancer. This novel regulatory link, as well as the marked reduction in patient survival time associated with increased glutamine pathway gene expression, suggests that targeting glutamine metabolism may have therapeutic potential in the treatment of ERBB2+ breast cancer

Les descendants d’immigrés à l’école

Les débats sur les origines des inégalités scolaires entre les élèves descendants d’immigrés et les « natifs » restent vifs. Pour certains, les politiques de démocratisation de l’enseignement secondaire, telles qu’elles se sont développées dans les pays européens dès le milieu du XXe siècle, ont suffi à éliminer la spécificité des destins scolaires des descendants d’immigrés. Dans cette perspective, les inégalités résiduelles ne seraient que la résultante des conditions sociales d’existence de ces élèves, souvent plus défavorisés au plan économique et culturel. Pour d’autres, ces interprétations en termes de discontinuité culturelle ne suffisent plus à rendre compte de la réalité dès lors que, selon les indicateurs choisis et les données mobilisées, le handicap des descendants d’immigrés persiste à milieu social égal. L’origine des inégalités serait alors à rechercher du côté du système éducatif lui-même, de la nature de l’offre de formation adressée aux différents types d’élèves, de la ségrégation entre établissements scolaires. Ces discriminations systémiques relèveraient alors plus des politiques scolaires elles-mêmes que de la distance culturelle et sociale entre familles et école. Ce dossier est une mise en perspective de ce débat au travers de quatre contributions basées sur des données comparatives nationales et internationales. Elles proposent des analyses originales des destins scolaires des élèves issus de l’immigration pour identifier les origines sociales et scolaires des inégalités de réussite. The debate about the roots of educational inequality between immigrant and native students is still going strong. Some believe that the secondary education democratisation policies that have been implemented in European countries since the mid-20th century have done enough to remove the specific features of immigrant students’ academic futures. From this point of view, any remaining inequality is merely due to these students’ living conditions as they often come from economically and culturally disadvantaged backgrounds. Others believe that this view, in terms of cultural discontinuity, is no longer appropriate given the reality as, based on selected indicators and data, educational inequality towards immigrants remains high, even when social background is controlled. The roots of inequality go back to the education system itself, to the curriculum available for different types of students and to segregation between schools. This systemic discrimination is therefore linked to school policies rather than to social and cultural distance between families and school. The four articles in this issue shall shed light on this debate using national and international comparative data. Immigrant students’ academic paths are analysed to identify the social and educational roots of achievement inequality