68 en flash-back

2018 aura été, dans son retour sur 1968, l’année de l’appel à témoins. La revue Écrire l’histoire a voulu participer à cette résurgence des souvenirs en demandant à des gens ordinaires plutôt qu’à de grands acteurs historiques de raconter l’image, le petit fait, l’anecdote qui leur venait en tête à propos des événements de cette année-là. La réunion de ces flash-back n’a pas de prétention scientifique. Elle a pour seule ambition de faire entendre une légère cacophonie : non pas la mémoire de 1968, mais des fragments hétéroclites qui en captent, fragilement, la trace.2018, as it looks back on 1968, will be characterised by roll calls of witnesses. Écrire l’histoire has sought to participate in this great resurgence of memories by asking ordinary people, rather than the great actors of history, to relate the image, the little detail, or the anecdote that comes to mind in relation to the events of that year. This collection of flash-backs makes no scientific claim. Its only goal is give voice to a mild cacophony: not the memory of 1968 as such, but some variegated fragments which capture, precariously, its traces

Measurement of mitochondrial respiration in permeabilized fish gills

Physiological investigations of fish gills have traditionally been centered on the two principal functions of the gills, gas exchange and ion regulation. Mitochondrion-rich cells (MRCs) are primarily found within the gill filaments of fish, and are thought to proliferate in order to increase the ionoregulatory capacity of the gill in response to environmentally-induced osmotic challenges. However, surprisingly little attention has been paid to the metabolic function of mitochondria within fish gills. Here we describe and validate a simple protocol for the permeabilization of fish gills and subsequent measurement of mitochondrial respiration rates in vitro. Our protocol requires only small tissue samples (8 mg), it exploits the natural structure of fish gills, does not require mechanical separation of the gill tissue (so is relatively quick to perform), and yields accurate and highly reproducible measurements of respiration rates. It offers great potential for the study of mitochondrial function in gills over a wide range of fish sizes and species

TREADMILL RUNNING: HOW LONG BEFORE BIOMECHANICS REACH A STEADY STATE?

The purpose of this study was to investigate short-term biomechanical changes during treadmill running and whether footwear influenced this adaptation. Forty-five adults with experience in treadmill running over the last year performed an 8.5-min trial at a self-selected speed with three different midsole hardness. Kinetics, kinematics, soft-tissue vibrations and electromyographic activity were recorded at minutes 0, 2, 4, 6 and 8. The fastest adjustments were an increase of active peak and foot inversion. Step frequency and lower limb stiffness decreased then plateaued at minute 6. Duty factor, contact and flight times didn’t reach a plateau. No time effect was found for passive peak, loading rate, leg muscle activity and soft-tissue vibrations. We recommend a minimum habituation period of 8-minutes to ensure that a maximum of biomechanical parameters reach a steady state

Mitochondrial function declines with age within individuals but is not linked to the pattern of growth or mortality risk in zebra finch

Mitochondrial dysfunction is considered a highly conserved hallmark of ageing. However, most of the studies in both model and non-model organisms are cross-sectional in design; therefore, little is known, at the individual level, on how mitochondrial function changes with age, its link to early developmental conditions or its relationship with survival. Here we manipulated the postnatal growth in zebra finches (Taeniopygia guttata) via dietary modification that induced accelerated growth without changing adult body size. In the same individuals, we examined blood cells mitochondrial functioning (mainly erythrocytes) when they were young (ca. 36 weeks) and again in mid-aged (ca. 91 weeks) adulthood. Mitochondrial function was strongly influenced by age but not by postnatal growth conditions. Across all groups, within individual ROUTINE respiration, OXPHOS and OXPHOS coupling efficiency significantly declined with age, while LEAK respiration increased. However, we found no link between mitochondrial function and the probability of survival into relatively old age (ca. 4 years). Our results suggest that the association between accelerated growth and reduced longevity, evident in this as in other species, is not attributable to age-related changes in any of the measured mitochondrial function traits

Genetically engineered probiotic E. coli Nissle to consume amino acids associated with orphan metabolic diseases

Orphan metabolic diseases are rare genetic defects that interfere with metabolism due to ineffective or missing enzymes. Two of them, Phenylketonuria (PKU) and Maple Syrup Urine Disease (MSUD) are defined by accumulation of amino acids to toxic levels due to defective metabolism of protein break down products. PKU is caused by a defect in the gene encoding phenylalanine hydroxylase (PAH). MSUD is caused by a defect in a multi-enzyme complex found in mitochondria called branched chain ɑ-ketoacid dehydrogenase “BCKDH”. Without the activity of these enzymes, the amino acid phenylalanine (Phe) in the case of PKU or the branched-chain amino acids leucine (Leu), isoleucine and valine for MSUD build up to neurotoxic levels in the blood and brain, leading to neurological deficits. Current treatment options focus on dietary protein restriction, are insufficient and, unfortunately, can lead to a failure to thrive. Lifelong compliance with a prescription diet is also a concern. We have genetically engineered Nissle, a probiotic strain of E. coli, to reduce serum phenylalanine and leucine levels in patients with PKU or MSUD; preclinical data supporting the activity of these strains are described. Please click Additional Files below to see the full abstract

Gender and class in Britain and France

This article examines the treatment of women's oppression in feminist theory, focusing on the engagement of second wave feminists with the concept of class and its relation to gender. This examination is carried out with reference to British and French feminisms, identifying the main trends and shifts that have developed over the last 35 years and noting that while these are undoubtedly influenced by a particular national context they are also shaped by increasing European integration and social, political and cultural exchanges at a global level. The authors find evidence of a number of similarities in the questions that feminist theorists have asked in Britain and France but also demonstrate that there are significant differences. They conclude that areas of convergent theoretical interests will extend along with cross-border flows of peoples and information

Engineering and manufacturing of probiotic E. Coli to treat metabolic disorder

The fields of synthetic biology and microbiome research developed greatly over the last decade. The convergence of those two disciplines is now enabling the development of new therapeutic strategies, using engineered microbes that operate from within the gut as living medicines. Inborn errors of metabolism represent candidate diseases for these therapeutics, particularly those disorders where a toxic metabolite causing a syndrome is also present in the intestinal lumen. Phenylketonuria (PKU), a rare inherited disease caused by a defect in phenylalanine hydroxylase (PAH) activity, is one such disease and is characterized by the accumulation of systemic phenylalanine (Phe) that can lead to severe neurological deficits unless patients are placed on a strict low-Phe diet. As an alternative treatment, Escherichia coli Nissle (EcN), a well-characterized probiotic, was genetically modified to efficiently import and degrade Phe (SYNB1618). The coupled expression of a Phe transporter with a Phe ammonia lyase (PAL) allows rapid conversion of Phe into trans-cinnamic acid (TCA) in vitro, which is then further metabolized by the host to hippuric acid (HA) and excreted in the urine. Experiments conducted in the enu2-/- PKU mouse model showed that the oral administration of SYNB1618 is able to significantly reduce blood Phe levels triggered by subcutaneous Phe injection. Decreases in circulating Phe levels were associated with proportional increases in urinary HA, confirming that Phe metabolism was caused by the engineered pathway in SYNB1618. Subsequent studies have shown that SYNB1618 is similarly operative in a non-human primate model, providing a translational link to inform future human clinical studies. Consistent with preclinical studies, recent Phase 1/2a clinical data demonstrate that oral administration of SYNB1618 resulted in significant dose-dependent production of biomarkers specifically associated with SYNB1618 activity, demonstrating proof-of-mechanism of this cell therapy

Engineering of probiotic E.coli to treat metabolic disorders

The fields of synthetic biology and microbiome research developed greatly over the last decade. The convergence of those two disciplines is now enabling the development of new therapeutic strategies, using engineered microbes that operate from within the gut as living medicines. Inborn errors of metabolism represent candidate diseases for these therapeutics, particularly those disorders where a toxic metabolite causing a syndrome is also present in the intestinal lumen. Phenylketonuria (PKU), a rare inherited disease caused by a defect in phenylalanine hydroxylase (PAH) activity, is one such disease and is characterized by the accumulation of systemic phenylalanine (Phe) that can lead to severe neurological deficits unless patients are placed on a strict low-Phe diet. As an alternative treatment, Escherichia coli Nissle (EcN), a well-characterized probiotic, was genetically modified to efficiently import and degrade Phe (SYN-PKU). The coupled expression of a Phe transporter with a Phe ammonia lyase (PAL) allows rapid conversion of Phe into trans-cinnamic acid (TCA) in vitro, which is then further metabolized by the host to hippuric acid (HA) and excreted in the urine. Experiments conducted in the enu2-/- PKU mouse model showed that the oral administration of SYN-PKU is able to significantly reduce blood Phe levels triggered by subcutaneous Phe injection. Decreases in circulating Phe levels were associated with proportional increases in urinary HA, confirming that Phe metabolism was caused by the engineered pathway in SYN-PKU. Subsequent studies have shown that SYN-PKU is similarly operative in a non-human primate model, providing a translational link to inform future human clinical studies. In addition to SYN-PKU, a second EcN strain was genetically engineered to rapidly import and degrade branched-chain amino acids (BCAAs) for the treatment of maple syrup urine disease (SYN-MSUD). MSUD, similar to PKU, is a rare genetic disorder caused by a defect in branched-chain ketoacid dehydrogenase activity leading to the toxic accumulation of BCAAs, particularly leucine, and their ketoacid derivatives. The controlled expression in SYN-MSUD of two BCAA transporters, a leucine dehydrogenase, a ketoacid decarboxylase and an alcohol dehydrogenase, result in the efficient degradation of BCAAs into branched-chain alcohols. In a mouse model of MSUD, the oral delivery of SYN-MSUD suppressed the increase in blood BCAAs level induced by a high-protein challenge and prevented the associated moribund phenotype, as measured by locomotor activity. In conclusion, the therapeutic effects observed with SYN-PKU and SYN-MSUD in pre-clinical studies support the further evaluation of engineered microbes as promising approaches for serious inborn errors of metabolism

Aneuploidy as a mechanism of adaptation to telomerase insufficiency

Cells’ survival is determined by their ability to adapt to constantly changing environment. Adaptation responses involve global changes in transcription, translation, and posttranslational modifications of proteins. In recent years, karyotype changes in adapting populations of single cell organisms have been reported in a number of studies. More recently, we have described aneuploidy as an adaptation mechanism used by populations of budding yeast Saccharomyces cerevisiae to survive telomerase insufficiency induced by elevated growth temperature. Genetic evidence suggests that telomerase insufficiency is caused by decreased levels of the telomerase catalytic subunit Est2. Here, we present experiments arguing that the underlying cause of this phenomenon may be within the telomerase RNA TLC1: changes in the expression of TLC1 as well as mutations in the TLC1 template region affect telomere length equilibrium and the temperature threshold for the induction of telomerase insufficiency. We discuss what lies at the root of telomerase insufficiency, how cell populations overcome it through aneuploidy and whether reversible aneuploidy could be an adaptation mechanism for a variety of environmental stresses

A time-resolved proteomic and prognostic map of COVID-19

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease