Institut de recherches cliniques de Montréal
Recent publications
First evidence shows that some parents engage in the health-endangering practice of (mis-)using prescription drugs to boost their children’s school performance. But little is known about parental perspectives on this phenomenon. This study aims to better understand parents’ perspectives on the non-medical use of prescription drugs to improve healthy children’s cognitive functioning. We conducted twelve semi-structured face-to-face interviews with a diverse sample of parents in Germany, and applied qualitative content analysis to explore their perspectives on instrumentalizing prescription drugs for improving the performance of healthy children, including their underlying knowledge (gaps), moral evaluations, evaluations of accompanied risks and benefits, opinions on potential motivators, and wishes regarding policy-making. The results show that parents typically believed themselves knowledgeable about such prescription drug (mis-)use, although they were not aware of anyone in their social environment taking them for enhancement. Parents generally considered such behavior to be morally reprehensible, cheating, and similar to doping in sports, and they typically claimed that no situation or occasion could motivate them to administer prescription drugs to their healthy children. Health risks (including side effects or addiction) were a typical expectation of drug use. That doctors should give such drugs to healthy young people was seen as unjustifiable. The results suggest that morality and risk–benefit evaluations of parents play a major role in their decision-making concerning this potentially risky instrumentalization of non-medical drugs. These insights are of distinct importance, especially for future research and further discussions on this topic, such as an evidence-based public dialog and ethics debates.
ARMC5 is implicated in several pathological conditions, but its function remains unknown. We have previously identified CUL3 and RPB1 (the largest subunit of RNA polymerase II (Pol II) as potential ARMC5-interacting proteins. Here, we show that ARMC5, CUL3 and RBX1 form an active E3 ligase complex specific for RPB1. ARMC5, CUL3, and RBX1 formed an active E3 specific for RPB1. Armc5 deletion caused a significant reduction in RPB1 ubiquitination and an increase in an accumulation of RPB1, and hence an enlarged Pol II pool in normal tissues and organs. The compromised RPB1 degradation did not cause generalized Pol II stalling nor depressed transcription in the adrenal glands but did result in dysregulation of a subset of genes, with most upregulated. We found RPB1 to be highly expressed in the adrenal nodules from patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) harboring germline ARMC5 mutations. Mutant ARMC5 had altered binding with RPB1. In summary, we discovered that wildtype ARMC5 was part of a novel RPB1-specific E3. ARMC5 mutations resulted in an enlarged Pol II pool, which dysregulated a subset of effector genes. Such an enlarged Pol II pool and gene dysregulation was correlated to adrenal hyperplasia in humans and KO mice.
Ethics designates a structured process by which important human values and meanings of life are understood and tackled. Therein, the ability to discuss openly and reflect on (aka deliberation) understandings of moral problems, on solutions to these problems, and to explore what a meaningful resolution could amount to is highly valued. However, the indicators of what constitutes a high-quality ethical deliberation remain vague and unclear. This article proposes and develops a pragmatist approach to evaluate the quality of deliberation. Deliberation features three important moments: (1) broadening and deepening the understanding of the situation, (2) envisioning action scenarios, (3) coming to a judgment based on the comparative evaluation of scenarios. In this paper, we propose seven criteria to evaluate ethical deliberations: (1) collaborative diversity, (2) experiential literacy, (3) organization of experiences, (4) reflective capacity to instrumentalize the experiences of others, (5) interactional creativity, (6) openness of agents, (7) quality of the reformulation of scenarios. These criteria are explained and applied to the three moments of deliberation. Based on these criteria, three kinds of outcomes for deliberations are identified and discussed: good ethical deliberations, partial ethical deliberations, bad ethical deliberations. Our proposal will guide researchers and practitioners interested in the evaluation of the quality of ethical deliberations. It provides a reference tool that allows them to identify the possible limitations of a deliberation and to implement actions aimed at correcting these limitations in order to achieve the desired qualitative objectives.
Background: Available studies comparing the efficacy of dual-hormone (DH)- algorithm-assisted insulin delivery (AID), single-hormone (SH)-AID and usual care on post-exercise overnight glucose in people with type 1 diabetes (T1D) have had different outcomes. By pooling data from all available studies, we aim to draw stronger conclusions. Methods: Data were pooled from two three-arm, open-label, randomized, controlled, crossover studies. Forty-one adults [median (Q1-Q3) age: 34.0 years (29.5, 51.0), mean HbA1c: 7.5 ± 1.0%] and 17 adolescents with type 1 diabetes [age: 14.0 (13.0, 16.0), HbA1c: 7.8 ± 0.8%] underwent DH-AID, SH-AID and usual care. Each intervention involved evening aerobic exercise (60-minutes). The primary outcome, time in range% (TIR%) overnight (00:00-06:00) post-exercise based on continuous glucose monitoring, was compared among treatments using linear mixed effect model or generalized linear mixed model. Results: Among adults, mean TIR% was 94.0% ± 11.9%, 83.1% ± 20.5% and 65.1% ± 37.0% during DH-AID, SH-AID and usual care intervention, respectively (P<0.05 for all between-group comparisons). DH-AID was superior to SH-AID and usual care, and SH-AID was superior to usual care regarding hypo- and hyperglycemia prevention but not glycemic variability. Among adolescents, DH-AID and SH-AID reduced dysglycemia, but not glycemic variability, better than usual care. Glycemic outcomes were similar between DH-AID and SH-AID. Conclusion: AID systems allow improved post-exercise nocturnal glycemic management than usual care for both adults and adolescents. DH-AID was better than SH-AID among adults but not adolescents.
Objective: Novel and minimally invasive neurotechnologies offer the potential to reduce the burden of epilepsy while avoiding the risks of conventional resective surgery. Few neurotechnologies have been tested in randomized controlled trials with pediatric populations, leaving clinicians to face decisions about whether to recommend these treatments with insufficient evidence about relevant risks and benefits. This study specifically explores the preferences of clinicians to treat pediatric drug resistant epilepsy (DRE) with novel neurotechnologies. Methods: A discrete-choice experiment (DCE) was designed to elicit preferences of clinicians with experience in treating children with DRE using novel neurotechnological interventions. Preferences for six key attributes used when making treatment decisions (chances of clinically significant improvement in seizures, major and minor risks from intervention, availability of evidence, financial burden for the family, and access to the intervention) were estimated using a conditional logit model. The estimates from this model were then used to predict adoption of existing novel neurotechnological interventions. Results: Sixty-eight clinicians completed the survey: 33 neurosurgeons, 28 neurologists, and 7 other clinicians. Most clinicians were working in the USA (74%), and the remainder (26%) in Canada. All attributes, apart from the nearest location with access to the intervention, significantly influenced preferences. The chance of clinically significant improvement in seizures was the most positive influence on clinician preferences, but low-quality evidence and a higher risk of major complications could offset these preferences. Of the existing neurotechnological interventions, vagus nerve stimulation was predicted to have the highest likelihood of adoption; deep brain stimulation had the lowest likelihood of adoption. Significance: Clinician preferences are primarily driven by the likelihood of achieving seizure freedom for their patient, but preferences for an intervention are largely eradicated if only low quality of evidence supporting the intervention is available. Until better evidence supporting the use of potentially effective, novel neurotechnologies becomes available, clinicians are likely to prefer more established treatments.
Activation of microglia in the spinal cord dorsal horn following peripheral nerve injury contributes to the development of pain hypersensitivity. How activated microglia selectively enhance the activity of spinal nociceptive circuits is not well understood. We discovered that following peripheral nerve injury, microglia degrade extracellular matrix structures, perineuronal nets (PNNs), in lamina I of the spinal cord dorsal horn. Lamina I PNNs selectively enwrap spinoparabrachial projection neurons, which integrate nociceptive information in the spinal cord and convey it to supraspinal brain regions to induce pain sensation. Degradation of PNNs by microglia enhances the activity of projection neurons and induces pain-related behaviors. Thus, nerve injury-induced degradation of PNNs is a mechanism by which microglia selectively augment the output of spinal nociceptive circuits and cause pain hypersensitivity.
Cellular functions are mostly defined by the dynamic interactions of proteins within macromolecular networks. Deciphering the composition of macromolecular complexes and their dynamic rearrangements is the key to get a comprehensive picture of cellular behavior and to understand biological systems. In the past two decades, affinity purification coupled to mass spectrometry has become a powerful tool to comprehensively study interaction networks and their assemblies. To overcome initial limitations of the approach, in particular, the effect of protein and RNA degradation, loss of transient interactors, and poor overall yield of intact complexes from cell lysates, various modifications to affinity purification protocols have been devised over the years. In this chapter, we describe a rapid single-step affinity purification method for the efficient isolation of dynamic macromolecular complexes. The technique employs cell lysis by cryo-milling, which ensures nondegraded starting material in the submicron range, and magnetic beads, which allow for dense antibody-conjugation and thus rapid complex isolation, while avoiding loss of transient interactions. The method is epitope tag-independent, and overcomes many of the previous limitations to produce large interactomes with almost no contamination. The protocol as described here has been optimized for the yeast S. cerevisiae.
Background COVID-19 is a threat to individual and global health, thus, reducing the disease's spread is of significant importance. However, adherence to behavioral measures against the spread of COVID-19 is not universal, even within vulnerable populations who are at higher risk of exposure to the virus or severe COVID-19 infection. Therefore, this study investigates how risk-group membership relates to adherence to COVID-19 behavioral measures, whether perceived threat of COVID-19 is a mechanism explaining this relationship, and whether knowledge about COVID-19 moderates these effects. Methods We conducted a web-based survey ( N = 4,096) representative of the adult population in Germany with regard to gender, age (18 to 74), and province. Therein, we assessed risk group membership with two indicators (risk of exposure to COVID-19 and risk of severe COVID-19 infection), perceived COVID-19 threat with the Perceived Coronavirus Threat Questionnaire, knowledge about COVID-19 with a knowledge test; and adherence to six behavioral measures to protect against the spread of COVID-19 (e.g., keeping distance, using mouth-nose protection, and following contact restrictions). We used moderated mediation models to test whether perceived threat mediates the relationship between risk-group membership and adherence and whether knowledge about COVID-19 moderates this relationship. Results We found that risk group members had more perceived COVID-19 threat and that knowledge about COVID-19 increased perceived threat. Moreover, risk group membership had a positive direct effect on adherence to most behavioral measures and risk group members with less knowledge about COVID-19 violated measures more frequently. Risk-group membership also had positive indirect effects on adherence via perceived COVID-19 threat. The moderated indirect effects of threat indicate that threat led to more adherence when knowledge was low, but lost relevance as knowledge increased. Conclusion The results may help to evaluate disease-regulation measures and to combat the pandemic more effectively. For example, increasing COVID-19 knowledge in the general population could increase adherence to COVID-19 behavioral measures. However, policy makers should be mindful that this could also have negative mental health implications as knowledge increases perceived COVID-19 threat.
The identification of FACT as a histone chaperone enabling transcription through chromatin in vitro has strongly shaped how its roles are envisioned. However, FACT has been implicated in essentially all aspects of chromatin biology, from transcription to DNA replication, DNA repair, and chromosome segregation. In this review, we focus on recent literature describing the role and mechanisms of FACT during transcription. We highlight the prime importance of FACT in preserving chromatin integrity during transcription and challenge its role as an elongation factor. We also review evidence for FACT's role as a cell-type/gene-specificregulator of gene expression and briefly summarize current efforts at using FACT inhibition as an anti-cancerstrategy.
Trogocytosis modulates immune responses, with still unclear underlying molecular mechanisms. Using leukemia mouse models, we found that lymphocytes perform trogocytosis at high rates with tumor cells. While performing trogocytosis, both Natural Killer (NK) and CD8+ T cells acquire the checkpoint receptor PD-1 from leukemia cells. In vitro and in vivo investigation revealed that PD-1 on the surface of NK cells, rather than being endogenously expressed, was derived entirely from leukemia cells in a SLAM receptor-dependent fashion. PD-1 acquired via trogocytosis actively suppressed NK cell antitumor immunity. PD-1 trogocytosis was corroborated in patients with clonal plasma cell disorders, where NK cells that stained for PD-1 also stained for tumor cell markers. Our results, in addition to shedding light on a previously unappreciated mechanism underlying the presence of PD-1 on NK and cytotoxic T cells, reveal the immunoregulatory effect of membrane transfer occurring when immune cells contact tumor cells.
Youth in foster care experience high rates of social, emotional, and behavioral challenges that are complicated by trauma and grief. To address these concerns, the current intervention study examines the efficacy of a newly developed peer grief support program, the L.Y.G.H.T. program, for youth in foster care, using an embedded sequential mixed methods design. Forty-two youth residing in three separate foster care group homes (“community sites”) in a southeastern state participated in this study. Youth were randomly assigned to either the treatment program or a waitlist control group. Baseline and post-intervention (after 6 weeks) assessments of the Children’s Hope Scale, the Inventory of Social Support, the Rosenberg Self-Esteem Scale, and the Strengths and Difficulties Questionnaire-Self Report were administered. After each weekly group, participants completed a survey to assess trauma-informed program environment and facilitators completed a survey to assess fidelity to the intervention. Focus groups (n = 3) were conducted at each of the community sites after the post-intervention assessments were completed. To examine program impact, we evaluated whether increases in well-being (i.e., social support, hopefulness, and self-worth) and decreases in total problem behaviors would be found for participants in the treatment group. Social support, hopefulness, and self-worth increased and total problems remained the same for youth in the treatment program. Large effects were found for program helpfulness, a trauma-informed program environment, and reduction in perceived problems. Focus group feedback explained why youth were initially interested in the program, perceived program benefits, program dislikes, barriers to program participation, recommendation of the program, and additional feedback. The findings suggest that the L.Y.G.H.T. program is an efficacious intervention which addresses loss and grief and enhances the well-being of youth in foster care who are grieving.
Utilising science and technology to maximize human performance is often an essential feature of military activity. This can often be focused on mission success rather than just the welfare of the individuals involved. This tension has the potential to threaten the autonomy of soldiers and military physicians around the taking or administering of enhancement neurotechnologies (e.g., pills, neural implants, and neuroprostheses). The Hybrid Framework was proposed by academic researchers working in the U.S. context and comprises "rules" for military neuroenhancement (e.g., ensuring transparency and maintaining dignity of the warfighter). Integrating traditional bioethical perspectives with the unique requirements of the military environment, it has been referenced by military/government agencies tasked with writing official ethical frameworks. Our two-part investigation explored the ethical dimensions of military neuroenhancements with military officers - those most likely to be making decisions in this area in the future. In three workshops, structured around the Hybrid Framework, we explored what they thought about the ethical issues of enhancement neurotechnologies. From these findings, we conducted a survey (N = 332) to probe the extent of rule endorsement. Results show high levels of endorsement for a warfighter's decision-making autonomy, but lower support for the view that enhanced warfighters would pose a danger to society after service. By examining the endorsement of concrete decision-making guidelines, we provide an overview of how military officers might, in practice, resolve tensions between competing values or higher-level principles. Our results suggest that the military context demands a recontextualisation of the relationship between military and civilian ethics. Supplementary information: The online version contains supplementary material available at 10.1007/s12152-022-09490-2.
Many services can assist autistic people, such as early intervention, vocational services, or support groups. Scholars and activists debate whether such services should be autism-specific or more general/inclusive/mainstream. This debate rests on not only clinical reasoning, but also ethical and social reasoning about values and practicalities of diversity and inclusion. This paper presents qualitative results from a mixed-methods study. An online survey asked autistic adults and parents of autistic people of any age in Canada, the United States, Italy, France, and Germany what types of services they prefer (autism-specific, mixed-disability, or general/inclusive/mainstream). This paper presents the advantages and disadvantages of different service types, identified through inductive thematic coding and organized into higher-level themes focusing on clinical, structural, societal, interpersonal, and personal aspects of services. Autism-specific services were praised for addressing autism needs, helping clinically, and providing interpersonal benefits of others understanding autism; general services were praised for inclusion, helping clinically, community obligations and awareness, and social skills development. Looking at the interaction of these different aspects in respondent narratives nuances debates about autism-specificity, with a complex interplay between clinical, interpersonal, and societal aspects. Clinical and social perspectives are not necessarily separate and opposed, but intertwined based on different understandings of inclusion. Compared to parents, adults focused more on harm/safety issues, enjoyment, and stereotyping among other themes, attending to personal themes. These findings do not identify one best service type, but suggest that determining the right service in a given context may be informed by definitions of and goals about inclusion.
Elevated plasma lipoprotein(a) (Lp(a)) is an independent, causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Lp(a) is formed in or on hepatocytes from successive non-covalent and covalent interactions between apo(a) and apoB, although the subcellular location of these interactions and the nature of the apoB-containing particle involved remain unclear. Sortilin, encoded by the SORT1 gene, modulates apoB secretion and LDL clearance. We used a HepG2 cell model to study the secretion kinetics of apo(a) and apoB. Over-expression of sortilin increased apo(a) secretion, while siRNA-mediated knockdown of sortilin expression correspondingly decreased apo(a) secretion. Sortilin binds LDL but not apo(a) or Lp(a), indicating that its effect on apo(a) secretion is likely indirect. Indeed, the effect was dependent on the ability of apo(a) to interact non-covalently with apoB. Overexpression of sortilin enhanced internalization of Lp(a), but not apo(a), by HepG2 cells, although neither sortilin knockdown in these cells or Sort1 deficiency in mice impacted Lp(a) uptake. We found several missense mutations in SORT1 in patients with extremely high Lp(a) levels; sortilin containing some of these mutations was more effective at promoting apo(a) secretion than wild-type sortilin, though no differences were found with respect to Lp(a) internalization. Our observations suggest that sortilin could play a role in determining plasma Lp(a) levels and corroborate in vivo human kinetic studies which imply that secretion of apo(a) and apoB are coupled, likely within the hepatocyte.
During development, highly specialized differentiated cells, such as pituitary secretory cells, acquire their identity and properties through a series of specification events exerted by transcription factors to implement a unique gene expression program and epigenomic state. The investigation of these developmental processes informs us on the unique features of a cell lineage, both to explain these features and also to outline where these processes may fail and cause disease. This review summarizes present knowledge on the developmental origin of pituitary corticotrope and melanotrope cells and on the underlying molecular mechanisms. At the onset, comparison of gene expression programs active in pituitary progenitors compared to those active in differentiated corticotropes or melanotropes indicated dramatic differences in the control of, for example, cell cycle. Tpit is the transcription factor that determines terminal differentiation of POMC lineages, both corticotropes and melanotropes, and its action involves this switch in cell cycle control in parallel with activation of cell‐specific gene expression. There is thus far more to making a corticotrope cell than just activating transcription of the POMC gene. Indeed, Tpit also controls implementation of mechanisms for big protein translation capacity and development of extensive secretory organelles. The corticotrope cell identity also includes mechanisms responsible for homotypic cell‐cell interactions between corticotropes and for privileged heterotypic cell interactions with pituitary cells of other lineages. The review also summarizes current knowledge on how a pioneer transcription factor, Pax7, remodels the epigenome such that the same determination transcription factor, Tpit, will implement the melanotrope program of gene expression. Finally, this canvas of regulatory mechanisms implementing POMC lineage identities constitutes the background to understand alterations that characterise corticotrope adenomas of Cushing's disease patients. The integration of all this data into a unified scheme will likely yield a scheme to globally understand pathogenic mechanisms in Cushing's disease. This article is protected by copyright. All rights reserved.
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Celia Jeronimo
  • Research Unit in Chromatin and Genomic Expression
Marlene Oeffinger
  • Research Division of Systems Biology and Medicinal Chemistry
Virginie Calderon
  • Bioinformatics Core Facility
Rachid Essalmani
  • Research Division of Neurobiology and Development
Charles Vadnais
  • Research Unit in Hematopoiesis and Cancer
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