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A “Nano-Robot” Built Entirely from DNA to Explore Cell Processes

Posted on by Léa Surugue

Scientists have designed a “nano-robot” made up of three DNA origami structures. © Gaëtan Bellot/Inserm

Constructing a tiny robot from DNA and using it to study cell processes invisible to the naked eye… You would be forgiven for thinking it is science fiction, but it is in fact the subject of serious research by scientists from Inserm, CNRS and Université de Montpellier at the Structural Biology Center in Montpellier[1]. This highly innovative “nano-robot” should enable closer study of the mechanical forces applied at microscopic levels, which are crucial for many biological and pathological processes. It is described in a new study published in Nature Communications.

Our cells are subject to mechanical forces exerted on a microscopic scale, triggering biological signals essential to many cell processes involved in the normal functioning of our body or in the development of diseases.

For example, the feeling of touch is partly conditional on the application of mechanical forces on specific cell receptors (the discovery of which was this year rewarded by the Nobel Prize in Physiology or Medicine).

In addition to touch, these receptors that are sensitive to mechanical forces (known as mechanoreceptors) enable the regulation of other key biological processes such as blood vessel constriction, pain perception, breathing or even the detection of sound waves in the ear, etc.

The dysfunction of this cellular mechanosensitivity is involved in many diseases – for example, cancer: cancer cells migrate within the body by sounding and constantly adapting to the mechanical properties of their microenvironment. Such adaptation is only possible because specific forces are detected by mechanoreceptors that transmit the information to the cell cytoskeleton.

At present, our knowledge of these molecular mechanisms involved in cell mechanosensitivity is still very limited. Several technologies are already available to apply controlled forces and study these mechanisms, but they have a number of limitations. In particular, they are very costly and do not allow us to study several cell receptors at a time, which makes their use very time-consuming if we want to collect a lot of data.

DNA origami structures

In order to propose an alternative, the research team led by Inserm researcher Gaëtan Bellot at the Structural Biology Center (Inserm/CNRS/Université de Montpellier) decided to use the DNA origami method. This enables the self-assembly of 3D nanostructures in a pre-defined form using the DNA molecule as construction material. Over the last ten years, the technique has allowed major advances in the field of nanotechnology.

This enabled the researchers to design a “nano-robot” composed of three DNA origami structures. Of nanometric size, it is therefore compatible with the size of a human cell. It makes it possible for the first time to apply and control a force with a resolution of 1 piconewton, namely one trillionth of a Newton – with 1 Newton corresponding to the force of a finger clicking on a pen. This is the first time that a human-made, self-assembled DNA-based object can apply force with this accuracy.

 

The team began by coupling the robot with a molecule that recognizes a mechanoreceptor. This made it possible to direct the robot to some of our cells and specifically apply forces to targeted mechanoreceptors localized on the surface of the cells in order to activate them.

Such a tool is very valuable for basic research, as it could be used to better understand the molecular mechanisms involved in cell mechanosensitivity and discover new cell receptors sensitive to mechanical forces. Thanks to the robot, the scientists will also be able to study more precisely at what moment, when applying force, key signaling pathways for many biological and pathological processes are activated at cell level.

“The design of a robot enabling the in vitro and in vivo application of piconewton forces meets a growing demand in the scientific community and represents a major technological advance. However, the biocompatibility of the robot can be considered both an advantage for in vivo applications but may also represent a weakness with sensitivity to enzymes that can degrade DNA. So our next step will be to study how we can modify the surface of the robot so that it is less sensitive to the action of enzymes. We will also try to find other modes of activation of our robot using, for example, a magnetic field,” emphasizes Bellot.

 

[1] Also contributed to this research: the Institute of Functional Genomics (CNRS/Inserm/Université de Montpellier), the Max Mousseron Biomolecules Institute (CNRS/Université de Montpellier/ENSCM), the Paul Pascal Research Center (CNRS/Université de Bordeaux) and the Physiology and Experimental Medicine: Heart-Muscles laboratory (CNRS/Inserm/Université de Montpellier).

Lancement de la campagne de recherche participative Science à la Pelle : trouver des médicaments sous nos pieds

Posted on by Graziella Cara

Do Some Cognitive Biases Contaminate Even Our Simplest Mental Mechanisms?

Posted on by Lea Roy

Enfants apprenant à écrire à l'école

©woodleywonderworks via Flickr

 

When we implement complex cognitive processes, for example when making decisions, we are subject to cognitive bias. But what about simpler processes, such as those involved in the most basic learning? In a new study analyzing data from all previous research in the field, researchers from Inserm and ENS-PSL show that not only are positivity and confirmation biases present even in the simplest human and animal cognitive processes, but also that incorporating them into learning algorithms would enhance their performance. This research, published in Trends in Cognitive Sciences, suggests that these biases could initially have been a very old evolutionary advantage.

Cognitive biases, such as positivity and confirmation biases, are known to influence our beliefs and decisions. Until recently, it was assumed that they were specific to so-called “high-level” cognitive processes, namely those that come into play when we reason about complex and uncertain proposals.  For example, it is well known that people overestimate the likelihood of desirable events (France winning the World Cup) and underestimate that of undesirable events (a marriage ending in divorce). 

In a study published in Trends in Cognitive Sciences, Stefano Palminteri, Inserm researcher at the ENS-PSL/Inserm Laboratory for Cognitive and Computational Neuroscience and Maël Lebreton, researcher at the Paris School of Economics, challenge this conception of the involvement of positivity and confirmation biases.

The researchers drew on the various existing data in the scientific literature on “reinforcement learning”. This is a basic cognitive process of learning through rewards and punishments that humans share with many animals. This literature review reveals that very simple reinforcement learning tests can reveal behavioral signatures of positivity and confirmation biases in people who are subjected to them. These biases appear to be much more common than previously thought and are even present in the simplest cognitive processes such as learning to make good decisions through trial and error (reward and punishment).

What is more, these biases do not seem to be exclusive to humans: the behavioral signatures also appear in similar tests conducted in animals. This suggests that these biases may have emerged during evolution in a common ancestor, long before the appearance of Homo sapiens, raising the question of why evolution has selected and maintained what may at first glance be perceived as processes that can generate seemingly irrational behavior.

Palminteri and Lebreton believe that they have identified part of the answer to this question through the findings of studies based on computerized simulations. These studies compared the performance of reinforcement learning algorithms – with some algorithms incorporating positivity and confirmation biases and others not. These simulations show that the presence of a confirmation bias in the algorithm actually enables it to learn more effectively in a wide range of situations. These biases could therefore actually promote survival, which would explain why they have not been corrected during the course of evolution.

The article opens up new avenues of research that would allow us to deepen our understanding of the cognitive biases and processes related to reinforcement learning. In particular, the researchers suggest exploring the role of these biases in the development and maintenance of pathological states, such as addiction and depression. These findings also suggest that including these biases in artificial intelligence algorithms could paradoxically improve their performance.

Long COVID: When Symptoms Persist Months after the First Wave

Posted on by Léa Surugue

During the first wave of COVID-19, participants from the Constances cohort completed two questionnaires to determine the presence of symptoms during the previous 15 days. Credits: Adobe Stock

Several months after infection with SARS-CoV-2, some patients are still having symptoms – a phenomenon known as “long COVID” or “post-COVID-19 condition”. Still poorly understood, scientists are now attentively studying long COVID in order to improve knowledge and offer patients the best possible treatment. Researchers from Inserm, Université Paris-Saclay and Sorbonne Université at the Pierre-Louis Institute of Epidemiology and Public Health, in collaboration with ANRS | Emerging Infectious Diseases, have used data from around 26,000 Constances cohort volunteers to identify the persistent symptoms most commonly reported by SARS-CoV-2 patients compared with the rest of the population. These are mainly loss of taste or smell, difficulty breathing and fatigue and are particularly seen in patients who experienced typical COVID symptoms at the time of infection. Their findings have been published in The Lancet Regional Health – Europe.

Many people report symptoms that persist for several months after infection with SARS-CoV-2. Still poorly understood, “long COVID” is currently the subject of rigorous research in order to better define its prevalence in the general population and decipher its underlying pathophysiological mechanisms.

The persistent symptoms most commonly described in the scientific literature include dyspnea (difficulty breathing), asthenia (fatigue), joint and muscle pain, cognitive complaints, digestive complaints, and anosmia/dysgeusia (loss of smell and taste).

Apart from anosmia/dysgeusia, these clinical manifestations are not specific to COVID-19 and may, for example, be related to other infections occurring during the same period or to more restricted access to health care during the pandemic.

In order to better understand and treat long COVID, it is therefore essential for scientists to determine which persistent symptoms are more specifically associated with SARS-CoV-2 infection than with other conditions.

A general population study

A new study published in The Lancet Regional Health has examined this issue. One of the aspects that makes this research original is that it was carried out in a general population cohort.

General population cohorts differ from cohorts constructed from samples of COVID patients (who, by definition, are all “symptomatic”, often with severe clinical forms or hospitalized), which are not representative of everyone with the infection.

General population cohorts therefore make it possible to understand public health problems through the creation of comparison groups, for example focusing on the severity of symptoms at the time of infection.

Another novel aspect is that the participants all underwent a serological test to screen for a history of SARS-CoV-2 infection. This differentiates this study from the majority of its counterparts, which focus on those having performed a PCR test and who have presented symptoms.

For example, this study compared the persistence of symptoms seven to eight months after the first wave of the pandemic in four groups of participants[1] distributed according to the symptoms they had during that first wave and their serological status (whether or not they had been infected with SARS-CoV-2). 

Long-term symptoms according to serological status

A total of 25,910 participants from the Constances cohort (see box) completed two questionnaires during the first wave of COVID-19 to determine the presence of symptoms during the fifteen days prior. They then underwent a serological test, between May and November 2020, to identify those who had been exposed to the virus.

Finally, between December 2020 and February 2021, they completed a third questionnaire, which looked at symptoms having persisted or persisting for at least two months. This questionnaire included the list of symptoms focused on during the first waves of questionnaires, as well as new symptoms presented by people with long COVID (problems with concentration and attention, chest pains, etc.).

The researchers compared the individuals having presented symptoms suggestive of acute respiratory infection based on the results of their serological test. They observed that symptomatic individuals seropositive for SARS-CoV-2 had more persistent anosmia/dysgeusia, dyspnea and fatigue than those who were seronegative. The frequency of the other symptoms was equivalent.

Links between symptoms at the time of infection and persistent symptoms

The researchers then explored the link between infection, acute symptoms, and persistent symptoms. The results of their statistical analyses show that SARS-CoV-2 mainly affects the persistence of symptoms if it induces certain symptoms during the acute phase of the infection.

“Our findings confirm the importance of the clinical expression of the initial infectious episode in the risk of developing persistent symptoms. They can help guide public policies by providing more accurate data on the type of persistent COVID-19 symptoms and encourage the development of strategies for more effective treatment. Promoting preventive therapies and approaches, such as vaccination, that reduce symptoms in the acute phase of the disease could also have a beneficial effect on long COVID,” the study authors noted.

These findings reflect the complexity of the mechanisms that can explain the persistent symptoms, emphasizing that these symptoms may be related to the virus, to the initial clinical presentation of the infection, and to other non-specific causes.

They also suggest the importance of conducting studies on post-infectious conditions, regardless of the micro-organism in question.

Further research is under way to understand the mechanisms behind long COVID and to quantify the extent to which these persistent symptoms can be attributed to SARS-CoV-2 infection

The Constances cohort

Constances is a large-scale French epidemiological cohort, composed of a representative sample of 220,000 adults aged 18 to 69 years at the time of their inclusion. Participants are asked to have a health check every four years and to complete an annual questionnaire. Each year, their data are matched with the French national health insurance databases. This large-scale cohort is supported by the National Health Insurance Fund and financed by the Investments for the Future Program.

The data collected, which concern health, socio-professional characteristics, use of health care services, and biological, physiological, physical and cognitive parameters, enable us to learn more about the determinants of many diseases.

Constances is one of three cohorts on which is based the SAPRIS-SERO project led by Inserm and ANRS | Emerging Infectious Diseases – a project which aims to quantify the incidence of SARS-CoV-2 in the French population on the basis of serological tests.

For more information: constances.fr

[1] The members of the first group of participants all had a positive COVID-19 serological test and had reported symptoms during the first wave. Those of the second group had a positive test but no symptoms. Those of the third group had a negative test and symptoms, while those of the fourth group were asymptomatic during the first wave and with a negative test.

HIV: The Antibodies of “Post-treatment Controllers”

Posted on by Léa Surugue

VIH

© Adobe Stock

A very small percentage of people with HIV-1, known as “post-treatment controllers” (PTCs), are able to control their infection after interrupting all antiretroviral therapy. Understanding the fundamental mechanisms that govern their immune response is essential in order to develop HIV-1 vaccines, novel therapeutic strategies to achieve remission, or both. A recent study investigated the humoral immune response – also known as antibody-mediated immunity – in some PTCs in whom transient episodes of viral activity were observed. The researchers have shown their humoral immune response to be both effective and robust, which could help to control the infection in the absence of treatment. The findings of this study, carried out in collaboration with teams from Institut Pasteur, Inserm and Paris Public Hospitals Group (AP-HP) and supported by ANRS | Emerging Infectious Diseases and the National Institutes of Health (NIH), were published in Nature Communications on April 11, 2022.

A very small percentage of people with HIV-1 and who received early treatment maintained over several years have the capacity to control the virus over the long-term when their treatment is interrupted. However, the mechanisms of this control have not been fully elucidated.  

The team of researchers, led by Dr. Hugo Mouquet, director of the Laboratory of Humoral Immunology at Institut Pasteur (partner research organization of Université Paris Cité), conducted an exhaustive study in PTCs in order to characterize their humoral response (i.e. their production of B cells and specific antibodies), compared with non-controllers.

The scientists have shown that the humoral immune response profiles vary according to the activity of the virus observed in the subjects.

In PTCs who experience short episodes in which the virus resumes low-level activity after interruption of treatment, transient exposure to the viral antigens induces:

  • a strong anti-HIV-1 humoral response, involving more frequent intervention of HIV-1 envelope-specific memory B cells;
  • the production of antibodies with a cross-neutralizing action and which possess “effector” antiviral activities in which the innate immune cells recognize the infected cells bound to the antibodies, thereby inducing their elimination;
  • the increase in the blood of atypical memory B cells and subpopulations of activated helper T cells.

This specific, multifunctional, and robust humoral response could help to control their infection in the absence of treatment.

However, other PTCs in whom the virus continuously remains undetectable after treatment interruption do not develop a strong humoral response. The control mechanisms in these patients continue to be investigated in the VISCONTI study.

The discovery of these two types of humoral immune response, which depend on the profile of the PTCs, sheds new light on the phenomenon of HIV control. For Dr. Mouquet, researcher at Institut Pasteur and principal investigator of the study, “these findings show that early antiretroviral treatment can facilitate the optimal development of humoral immune responses, in some cases countering viral rebound after treatment interruption.” The example of the immune response of the PTCs having short episodes of “awakening” of the virus could even inspire novel therapeutic or vaccine strategies.

ANRS VISCONTI: to improve understanding of the HIV control mechanisms in “post-treatment controllers”

The “post-treatment controllers” whose samples were used for this research are part of the VISCONTI (Viro-Immunological Sustained COntrol after Treatment Interruption) study, coordinated by Dr. Asier Sáez-Cirión (Institut Pasteur) and Dr. Laurent Hocqueloux (Orleans Regional Hospital) and supported by ANRS for several years. This is the largest cohort of long-term “post-treatment controllers”.

It includes 30 patients who had received early treatment that was maintained for several years. Upon interruption of their antiretroviral therapy, they are able to control their viremia for a period exceeding 20 years in some cases. VISCONTI therefore provides the proof of concept of a possible and sustained state of remission for HIV-1-infected patients. It has paved the way for the development of novel therapies that target remission from the infection – if not its eradication. The objective is to enable people living with HIV-1 to stop their antiretroviral treatment on a lasting basis, while maintaining viremia at the lowest level and avoiding the risk of transmission of the virus.

MICA: A New Immune Response Gene That Predicts Kidney Transplant Failure

Posted on by Léa Surugue

Histological image of a kidney transplant rejection mediated by antibodies. Sophie Caillard/Jérome Olagne (Inserm U1109).

Although a kidney transplant is the only curative treatment for end-stage kidney disease, the risk of the patient’s body rejecting the graft means that success is not guaranteed. To reduce this risk, physicians are now able to look at a certain number of genetic and immunological parameters in order to evaluate the histocompatibility between donor and recipient – i.e. how compatible their organs and tissues are. Nevertheless, rejections continue to remain common, and many are unexplained. In a new study, researchers from Inserm, Université de Strasbourg and Strasbourg University Hospitals at Unit 1109 “Molecular Immunology and Rheumatology”, and their partners from the Laboratory of Excellence (LabEx) Transplantex, report that the MICA gene is a new histocompatibility gene, in that it helps to better explain and predict the success or failure of a kidney transplant. Their findings have been published in Nature Medicine.

Kidney transplant is currently the best way to treat patients with end-stage kidney disease. In France, an average of around 4,000 kidney transplants are performed each year (around 20,000 in the US). The kidneys mainly come from deceased donors, although the number of kidneys from living donors has been gradually increasing each year over the last two decades.

The possibility of rejection of the graft considered “foreign” by the recipient’s body is currently the main limitation of this procedure. While the use of immunosuppressant drugs[1] helps to reduce the risk, it does not eliminate it completely. “Chronic” rejection, which occurs over the years following the transplant, remains a major problem.

The discovery of the HLA system in the mid-20th century by French researcher Jean Dausset and his colleagues has enabled major advances. It is a set of proteins coded by the HLA genes – proteins which are present on the surface of our cells, particularly white blood cells.

Highly diverse and specific to each individual, this system makes it possible to assess the histocompatibility between donors and recipients – i.e. how compatible their organs and tissues are. The closer the HLA genes between donors and recipients, the lower the risk of rejection.

However, even when donor and recipient HLA genes are compatible, unexplained transplant rejections still occur. This phenomenon suggests that other as yet unidentified histocompatibility genes may play a role.

A role for the MICA gene

Researchers from Inserm, Université de Strasbourg and Strasbourg University Hospitals and their partners from LabEx Transplantex were therefore interested in a gene discovered almost thirty years ago by Seiamak Bahram[2] who coordinated this new research.

This gene, called MICA, codes for a protein expressed on several cell types. Previous studies had already suggested that this gene was important in predicting the outcome of a transplant, but the numbers of patients studied were insufficient (among other methodological limitations) in asserting that it was a histocompatibility gene. Furthermore, these studies did not focus on the entire MICA system, that is to say on both genetics (histocompatibility) and the serological aspects (presence of anti-MICA antibodies in the recipient’s blood).

In this latest study, the team studied MICA in over 1,500 kidney transplant recipients and their donors. Analyses of the MICA gene sequences show that when recipients and donors have a different version of the gene, the survival of the graft is reduced.

Furthermore, the researchers show that these MICA gene incompatibilities are responsible for the synthesis of antibodies directed against the donor’s MICA proteins, which are involved in transplant rejection. These antibodies are produced when the donor’s MICA proteins differ excessively from those of the recipient.

These findings suggest that MICA is a relevant histocompatibility gene to consider when envisaging a transplant, and that testing for anti-MICA antibodies may also be useful in predicting the success or failure of the graft. They must now be validated in large-scale prospective studies in which MICA will be considered in the same way as classic HLA genes.

“Following this research, we can now consider the inclusion in routine clinical practice of MICA gene sequencing and the identification of anti-MICA antibodies in patients prior to transplantation to assess histocompatibility with the donor and post-transplant to improve the prevention of rejection. Finally, we also envisage studying the role of MICA in the transplantation of other solid organs, such as the heart, lung and liver,” emphasizes Seiamak Bahram.

 

[1] Treatments that limit the action of the immune system used in autoimmune diseases and transplants.

[2] University Professor-Hospital Practitioner, Director of Inserm Unit 1109 and LabEx Transplantex, and Head of the Department of Clinical Immunology Laboratory at Strasbourg University Hospitals.

Significant Increase in Infant Mortality in France

Posted on by Tatiana Marotta

In France, for the first time in peacetime, the infant mortality rate has risen significantly in the last ten years. ©Adobe Stock

The infant mortality rate (IMR) is a key indicator of population health. In the absence of updated data on the statistical trends of this indicator in France, researchers from Inserm, Université de Paris, the Paris public hospitals group (AP-HP) and Nantes University Hospital, in collaboration with teams from the University of California, analyzed civil registry data from the French National Institute of Statistics and Economic Studies (INSEE) from 2001 to 2019. They identified a significant increase in the IMR since 2012, thereby setting France apart from other high-income countries. The findings, published in The Lancet Regional Health – Europe, reflect the importance of more in-depth research into the precise causes of these 1200 excess deaths observed each year in France before one year of age.

The United Nations have made one of its priority objectives the elimination of preventable deaths in children by 2030. Given that the vast majority of child deaths occur during the first year of life, the infant mortality rate (IMR)1 is used to track progress towards this goal.

IMR serves as a key indicator of population health, given its strong relationship with the socio-economic development and quality of preventive and curative care in the country. In some high-income countries, such as Finland and Sweden, the IMR has been continuously decreasing since World War II. In other countries, such as France, this decrease appears to be slowing down.

Scientists from Inserm, Université de Paris, the Paris public hospitals group (AP-HP), Nantes University Hospital and the University of California wanted to go further in the statistical analyses of the evolution of the French IMR, and more specifically over the 2001 to 2019 period.

During this study period, the deaths of 53,077 infants were recorded for 14,622,096 live births, giving an average IMR of 3.63/1,000 (4.00 for boys, 3.25 for girls). Around one quarter of the deaths (24.4%) occurred during the first day of life and half (47.8%) in the early neonatal period – the first week following birth.

An in-depth statistical analysis identified two inflexion points, in 2005 and 2012 (see figure above). The IMR saw a sharp decrease from 2001 to 2005, and then a slower decrease from 2005 to 2012. From 2012, a significant 7% increase in the IMR was observed. This meant that infant mortality rose from 3.32 in 2012 to 3.56 deaths per 1,000 live births in 2019. Sensitivity analyses2 showed this trend to be unrelated to changes in registering practices or changes in medical practices for the management of newborns with serious conditions. Subgroup analyses showed this increase to be mainly due to an increased IMR in the early neonatal period.

“Thanks to in-depth statistical analyses, we have identified a significant increase in the infant mortality rate in France since 2012. When comparing the data against other European countries with similar economies, such as Sweden and Finland, we observe that every year in France there is an excess of around 1,200 deaths of children under one year of age,” explains Prof. Martin Chalumeau, last author of the study. “It is essential to be able to explore in detail the causes of this increase by having, for example, systematic information on the specific medical and social circumstances of these deaths and by making this population, which is the most vulnerable, a real research and public health priority, which is not the case at present,” the researcher concludes.

1 Infant mortality rate (IMR) is defined as the number of deaths of children under one year of age (D0-D364) per 1,000 live births over a given period

2 Additional analyses to support the robustness of the main analyses

A Gene Therapy Studied in Steinert’s Disease

Posted on by Léa Surugue

Steinert’s disease is caused by the abnormal repetitions of a small DNA sequence in the DMPK gene. ©Unsplash

Myotonic dystrophy type 1 (DM1) or Steinert’s disease is a rare and debilitating genetic neuromuscular disease affecting multiple organs and with a fatal outcome. No treatment is available at present. Encouraged by previous research into its molecular causes, researchers from Inserm, CNRS, Sorbonne Université, Lille University Hospital and Université de Lille, in partnership with the Institute of Myology, at the Center for Research in Myology and the Lille Neuroscience & Cognition center, have developed and tested a promising gene therapy that acts directly at the origin of the disease. Initial findings published in Nature Biomedical Engineering show correction of molecular and physiological alterations in mouse skeletal muscle1.

Myotonic dystrophy type 1 (DM1), otherwise known as Steinert’s disease, is a rare, hereditary and genetic neuromuscular condition affecting around 1 in 8,000 people. Debilitating and fatal, it is referred to as a “multisystem” condition because it simultaneously affects the muscles (muscle weakening and atrophy called “dystrophy”; muscle relaxation impairment called “myotonia”) and other organs (cardiorespiratory, digestive and nervous systems, etc.). The expression and course of the disease vary from one patient to the next and no treatment exists as yet.

It is caused by the abnormal repetition of a small DNA sequence (triplet CTG2) in the DMPK (DM1 Protein Kinase) gene located on chromosome 19. In healthy individuals, this sequence is present but repeated between 5 and 37 times. However, in patients with DM1, a mutation occurs whereby the number of triplets increases, producing up to several thousand repetitions.

About the mechanisms enabling gene expression

To obtain the production of a protein, a gene (located in the cell nucleus) is first transcribed into a molecule of RNA. To become a messenger RNA (mRNA), it undergoes maturation, particularly involving splicing. This basically means that the molecule is cut into pieces, some of which are eliminated and others attached. Thanks to this finely regulated process, one gene can lead to the synthesis of different mRNA and therefore of different proteins. After splicing, the mature mRNA will eventually be translated into protein, outside of the cell nucleus.

In Steinert’s disease, the mutated gene is transcribed but the mutant mRNA are retained in the cell nuclei as characteristic aggregates. In the cells of people with DM1, the MBNL1 proteins that normally bind to certain RNA in order to regulate their splicing and maturation are “captured” by the RNA that carry the mutation.

Thus sequestered in the aggregates, it is impossible for them to perform their functions, resulting in the production of proteins that function less well or not at all, some of which have been linked to clinical symptoms.

The team led by CNRS Research Director Denis Furling at the Myology Research Center (Inserm/Sorbonne Université/Institute of Myology) in association with that of Nicolas Sergeant, Inserm Research Director at the Lille Neuroscience & Cognition Centre (Inserm/Université de Lille/Lille University Hospital), focused on a therapeutic strategy to restore the initial activity of MBNL1 in skeletal muscle cells expressing the mutation responsible for Steinert’s disease.

To do this, the scientists engineered modified proteins that present, like the protein MBNL1, binding affinities for the RNA carrying the mutation and as a consequence act as a decoy for these RNA.

When expressing these decoy proteins in vitro in muscle cells from patients with DM1, they observed that they were captured by the mutated RNA instead of the MBNL1 proteins. The latter were then released from the aggregates of mutated RNA and regained their normal function. As a result, the splicing errors initially present in these cells disappeared. Finally, the mutated RNA bound to the decoy proteins proved to be less stable and could be more easily and effectively eliminated by the cell.

Aggregates of mutant DMPK-RNA containing pathological triplet (red) repetitions visualized by FISH-immunofluorescence in the nuclei (blue) of muscle cells (green) isolated from patients with Myotonic dystrophy type1 © Denis Furling and Nicolas Sergeant

The research team then transposed this technique into an animal model in order to verify the validity of this approach in vivo. With the help of viral vectors used in gene therapy, the decoy proteins were expressed in the skeletal muscle of mouse models of Steinert’s disease. In these mice, a single injection was effective, over a long period of time and with few side effects, in correcting the muscle damage associated with the disease, particularly the splicing errors, myopathy and myotonia.

“Our findings highlight the efficacy on Steinert’s disease symptoms of a gene therapy based on the bioengineering of RNA-binding decoy proteins with strong affinity for the pathological repetitions present in the mutated RNA, in order to release the MBNL1 proteins and restore their regulatory functions,” declares Furling. However, the authors point out that additional studies are needed before this therapy can be transposed into a clinical study. “This research paves the way for the development of therapeutic solutions in the context of other diseases in which pathological RNA repetitions cause splicing regulation dysfunction,” concludes Sergeant.

 

1 The striated skeletal muscle is the muscle that is attached to the skeleton by tendons and which, due to its ability to contract, enables the performance of precise movements in a well-defined direction.

2 The coding sequence of a gene consists of the chaining of different combinations of four nucleic acids: adenine, guanine, cytosine, and thymine (replaced by uracil in RNA). These are organized in triplets (or codons) whose correct “reading” by the cell machinery enables the expression of a protein.

When narcolepsy makes creative

Posted on by Graziella Cara

©Adi Goldstein/ Unsplash

Sleeping we make it more creative? The study of narcolepsy, which enjoy privileged access to REM sleep, could provide key information to understand this phenomenon. A team including doctors from the hospital Pitié-Salpêtrière AP-HP and researchers from Inserm, CNRS and Université Sorbonne within the Institute for Brain and Spinal Cord Disorders, in collaboration with a team University of Bologna in Italy, revealed the existence of a greater creativity in patients with narcolepsy. The results of the study suggest a link between a particular phase of sleep, REM sleep, and creative abilities. This important advance, published in the journal Brain May 29, 2019, opens new avenues in understanding the cognitive functions of sleep and mechanisms of creative thinking.

Narcolepsy is a rare sleep disorder that affects approximately 0.02% of the general population. It is characterized by uncontrollable sleep phases. These sleepiness have the distinction of often begin immediately by a particular phase of sleep, REM sleep, a situation not to encounter in normal times.

Indeed, our sleep consists of several stages and REM sleep is always preceded by a slow phase of sleep. So it usually sleep at least an hour before accessing this particular sleep. Narcoleptic people therefore have privileged access to REM sleep. They also have many parallels symptoms associated with REM sleep, as if they existed in them a porous barrier between wakefulness and that sleep phase. For example, the majority of them are lucid dreamers, that is to say conscious dreaming when they are dreaming and can sometimes influence the dream scenario. If more than half of the adult population reported having made a lucid dream at least once in his life, regular lucid dreamers (several times a week) are very rare.

Data from the current literature suggest that either nap including REM sleep is followed by an increased period of greater mental flexibility to solve problems. Narcoleptic individuals with privileged access to this sleep phase, would there be a long-term effect on their creativity?

“By meeting regularly with narcoleptic patients in my service, I noticed they seemed more change in creative activities than average; not only in their careers but also in their leisure or their thinking. “Says Dr. Isabelle Arnulf, head of the Sleep pathology department at the Pitié-Salpêtrière, AP-HP. From this observation was born the idea of exploring the creative capabilities of these patients with regard to their particular access to REM sleep.

A study by Celia Lacaux, a researcher at the Sorbonne University, and Delphine Oudiette researcher at Inserm, within the department of sleep pathologies of the Pitié-Salpêtrière Hospital AP-HP led by Prof. Isabelle Arnulf to ICM, tested in collaboration with a team from the University of Bologna in Italy, the creative capacities of 185 narcoleptic individuals and 126 control individuals.

Defining and measuring creativity is not an easy task. In neuroscience, it can be defined as the ability to produce something both original and adapted to the constraints. To evaluate and obtain the fullest possible extent, the researchers used two methods:

  • A “subjective” measure based on creativity questionnaires in 185 narcoleptic subjects and 126 control subjects: a test “creative profiles” focused on the personality and creative profile, and a test of “creative fulfillment” on personal achievements participants in various fields of the arts and sciences, cinema writing, through humor, cooking or architecture.

 

  • A measure ‘objective’ creative performance through a “paper and pencil” test for two hours, called EPOC (Evaluation of the Creative Potential) in 30 patients and 30 controls. It assesses the two main dimensions of creativity: divergent thinking which demand from a stimulus to generate the most possible responses; and convergent thinking, which requires the integration of several objects in a single generation, coherent and original.

Narcoleptic individuals generally received higher scores than the control subjects, both objective measures and subjective. ”  If narcoleptic subjects had higher scores than control subjects, only some of them really stood out in terms of creative fulfillment. This suggests that we really encourage narcoleptic people realize their potential. “Said Delphine Oudiette, Inserm researcher at the MHI, who led the study. ”  Moreover, among people with narcolepsy, the subgroup of lucid dreamers obtenaitles highest scores of creative profiles test, suggesting a role of dreams in the creative abilities. “

This increased creativity could be explained by the privileged access to REM sleep and dreams enjoyed narcoleptic people and gives them the opportunity to “incubate” their ideas during brief naps during the day.

”  This is a strong argument to say that regular access to REM sleep and dreams promotes creativity. Sleep on it, you will find a solution! It is also the first time we show that narcoleptic subjects are better than average in an area as important as creativity, bringing the same positive note to this difficult disease to live with. “Celia Lacaux concludes, first author of the study. Further work will be needed to confirm this but these early results provide important clues to understanding the functions of REM sleep and dreams.

Consumption of ultra-processed food and risk of cardiovascular disease

Posted on by Graziella Cara

©Photo Christopher Flowers / Unsplash

In an article published May 30, 2019 in the British Medical Journal, researchers from Inserm, Inra, Université Paris 13 and Cnam in the Nutritional Epidemiology Research Team (EREN) report an increased risk of cardiovascular disease in consumers of ultra-processed foods in the NutriNet-Santé cohort.

In recent decades, dietary habits have shifted towards an increased consumption of ultra-processed foods (see boxed text below), which currently account for over half of the total daily energy intake in many western countries. Such foods are often characterized by lower nutritional quality, in addition to the presence of additives, neoformed compounds and substances from packaging and other contact materials.

Recent studies have shown links between the consumption of ultra-processed foods and an increased risk of dyslipidemia, overweight, obesity, and hypertension.

While the Nutritional Epidemiology Research (EREN) team researchers have already observed links between the consumption of such foods and the risk of cancer, mortality, depression symptoms and functional gastrointestinal disorders, no epidemiological studies had up until now investigated the risk of cardiovascular disease. However, this has changed, thanks to the NutriNet-Santé cohort study by the EREN team – and more specifically by epidemiologist and PhD candidate Dr. Bernard Srour, led by Inserm Research Director Dr. Mathilde Touvier, in collaboration with the University of São Paulo in Brazil.

Over 100,000 participants from the French NutriNet-Santé cohort (followed up between 2009 and 2018) were included. On entry into the study, dietary intakes were collected using repeated 24-hour dietary records (on average, 6 per participant), designed to register their usual consumption of 3,300 different foods and drinks. These were categorized by degree of processing using the NOVA classification (see boxed text below).

During the follow-up period, ultra-processed food intake was found to be linked to a higher risk of cardiovascular disease (n = 1409 cases out of the 105,159 participants), particularly coronary heart disease (n = 665 cases), as well as cerebrovascular disease (n = 829 cases).

An absolute increase of 10% in the proportion of ultra-processed foods in the diet (for example, when comparing two individuals with diets consisting of 15% and 25% of ultra-processed foods, respectively) was linked to a 12% increase in the risk of overall cardiovascular disease (13% for coronary heart disease and 11% for cerebrovascular disease).

This observational study in itself does not enable a causal relationship to be established. However, in addition to the prospective design of the study, the results take into account a large number of sociodemographic and lifestyle factors, including age, sex, smoking status, alcohol consumption, educational level, physical activity and weight, metabolic comorbidities and family history. The results obtained also show that the lower overall nutritional quality of ultra-processed foods may not be the only factor involved.

The nutritional guidelines published recently by the French Public Health Agency (2019) recommend limiting the consumption of ultra-processed foods and opting for unprocessed or minimally processed foods. This is in line with the High Committee for Public Health objective of reducing by 20% the consumption of ultra-processed foods in France by 2022.

Definition and examples of ultra-processed foods

Food and drinks are assigned to one of the four groups in the NOVA classification, based on their degree of processing (unprocessed or minimally processed foods, processed culinary ingredients, processed foods, ultra-processed foods). This study focused on the “ultra-processed foods” group, which includes, for example, sugary and artificially-sweetened soft drinks, vegetables preserved with the addition of sauces containing food additives, vegetable nuggets reconstituted with the addition of additives, confectionery and any processed products with the addition of preservatives other than salt (for example, nitrites), as well as food products made mostly or entirely from sugar, oils and fats and other substances not used in culinary preparations, such as hydrogenated oils and modified starches. Industrial processes notably include hydrogenation, hydrolysis, extruding, and pre-processing by frying. Colors, emulsifiers, texturizing agents, non-sugar sweeteners and other additives are often added to these products.

Examples:

– Salted red or white meats are considered “processed foods”, whereas smoked meats and/or with added nitrites and preservatives, such as sausages and ham, are considered “ultra-processed foods”.

– Liquid soups in cartons prepared using just vegetables, herbs and spices are considered “processed foods” whereas dried soup mixes are considered “ultra-processed foods”.

 

NutriNet-Santé is a public health study coordinated by the Nutritional Epidemiology Research Team (EREN, Inserm U1153 / Inra U1125 / Cnam / Université Paris 13) which, thanks to the commitment and loyalty of over 160,000 participants (known as “Nutrinautes”), advances research into the links between nutrition (diet, physical activity, nutritional status) and health. Launched in 2009, the study has given rise to over 160 international scientific publications. To mark its 10-year anniversary, a call to enroll new participants is being launched so that together we can continue to further research into the relationship between nutrition and health.

By devoting a few minutes per month to answering various online questionnaires relating to diet, physical activity and health, participants contribute to furthering knowledge of the links between diet and health. With this civic gesture, we can each easily participate in research and, in just a few clicks, play a major role in improving the health of all and the wellbeing of future generations. These questionnaires can be found on the secure platform www.etude-nutrinet-sante.fr

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