Directing peptide crystallization through curvature control of nanotubes ‡

International audienceIn the absence of efficient crystallization methods, the molecular structures of fibrous assemblies have so far remained rather elusive. In this paper, we present a rational method to crystallize the lanreotide octapeptide by modification of a residue involved in a close contact. Indeed, we show that it is possible to modify the curvature of the lanreotide nanotubes and hence their diameter. This fine tuning leads to crystallization because the radius of curvature of the initially bidimensional peptide wall can be increased up to a point where the wall is essentially flat and a crystal is allowed to grow along a third dimension. By comparing X-ray diffraction data and Fourier transform Raman spectra, we show that the nanotubes and the crystals share similar cell parameters and molecular conformations, proving that there is indeed a structural continuum between these two morphologies. These results illustrate a novel approach to crystallization and represent the first step towards the acquisition of an Å-resolution structure of the lanreotide nanotubes β-sheet assembly

Champ de pression non isotrope approchant le champ des contraintes d'indentation d'un verre

Selon Yoffe (1982), les contraintes générées lors de l'indentation d'un verre relèvent d'une «plasticité non-orthodoxe» au sens d'une déformation irréversible non isovolume. Intervient un phénomène de densification où sa définition simple d'une inclusion sphérique tronquée équivalente utilise un champ uniforme de pression non isotrope approchant celui des contraintes «élasto-pseudo-plastique-densifiant». Un tel champ se compose d'un écrasement vertical réparti sur une surface circulaire et d'une expansion radiale; il approche le champ irréversible assimilé à la superposition du champ élastique de Boussinesq (1885) et d'un champ «d'ampoule». L'approximation de cette équivalence entre champ de pression uniforme non isotrope et champ élasto-plasto-densifiant est obtenue par troncature d'une série de Fourier; nos résultats semi-analytiques s'efforcent de dépendre explicitement du coefficient de Poisson et incitent à de futurs développements expérimentaux et théoriques

Confining Trypanosoma brucei in emulsion droplets reveals population variabilities in division rates and improves in vitro cultivation

Trypanosome parasites are infecting mammals in Sub-Saharan Africa and are transmitted between hosts through bites of the tsetse fly. The transmission from the insect vector to the mammal host causes a number of metabolic and physiological changes. A fraction of the population continuously adapt to the immune system of the host, indicating heterogeneity at the population level. Yet, the cell to cell variability in populations is mostly unknown. We develop here an analytical method for quantitative measurements at the single cell level based on encapsulation and cultivation of single-cell Trypanosoma brucei in emulsion droplets. We first show that mammalian stage trypanosomes survive for several hours to days in droplets, with an influence of droplet size on both survival and growth. We unravel various growth patterns within a population and find that droplet cultivation of trypanosomes results in 10-fold higher cell densities of the highest dividing cell variants compared to standard cultivation techniques. Some variants reach final cell titers in droplets closer to what is observed in nature than standard culture, of practical interest for cell production. Droplet microfluidics is therefore a promising tool for trypanosome cultivation and analysis with further potential for high-throughput single cell trypanosome analysis

Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer's disease

: Microtubules play fundamental roles in the maintenance of neuronal processes and in synaptic function and plasticity. While dynamic microtubules are mainly composed of tyrosinated tubulin, long-lived microtubules contain detyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination cycle is a key player in the maintenance of microtubule dynamics and neuronal homeostasis, conditions which go awry in neurodegenerative diseases. In the tyrosination/detyrosination cycle, the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidases and re-added by tubulin tyrosine ligase. Here we show that tubulin tyrosine ligase hemizygous mice exhibit decreased tyrosinated microtubules, reduced dendritic spine density, and both synaptic plasticity and memory deficits. We further report decreased tubulin tyrosine ligase expression in sporadic and familial Alzheimer's disease, and reduced microtubule dynamics in human neurons harboring the familial APP-V717I mutation. Finally, we show that synapses visited by dynamic microtubules are more resistant to oligomeric amyloid β peptide toxicity and that expression of tubulin tyrosine ligase, by restoring microtubule entry into spines, suppresses the loss of synapses induced by amyloid β peptide. Together, our results demonstrate that a balanced tyrosination/detyrosination tubulin cycle is necessary for the maintenance of synaptic plasticity, is protective against amyloid β peptide-induced synaptic damage, and that this balance is lost in Alzheimer's disease, providing evidence that defective tubulin retyrosination may contribute to circuit dysfunction during neurodegeneration in Alzheimer's disease

A parsimonious oscillatory model of handwriting

International audienceWe propose an oscillatory model that is theoretically parsimonious, empirically efficient and biologically plausible. Building on Hollerbach’s (Biol Cybern 39:139–156, 1981) model, our Parsimonious Oscillatory Model of Handwriting (POMH) overcomes the latter’s main shortcomings by making it possible to extract its parameters from the trace itself and by reinstating symmetry between the x and y coordinates. The benefit is a capacity to autonomously generate a smooth continuous trace that reproduces the dynamics of the handwriting movements through an extremely sparse model, whose efficiency matches that of other, more computationally expensive optimizing methods. Moreover, the model applies to 2D trajectories, irrespective of their shape, size, orientation and length. It is also independent of the endeffectors mobilized and of the writing direction

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Internalized activities

International audienceThis paper argues that interactive mental processes in humans have a natural tendency to replay internally and cyclically, a typical example being the tunes that run 'in our head' for hours. The existence of these 'internalized activities' may be shown by both simple introspection and neurological experiments, which also reveal that they occur in all sensory modalities and involve everything from perception to more abstract activities. We will show that this hypothesis provides new ways to explain 1-how real activity is guided by similar internalized activities, 2-how goals are represented to an agent by persistent internalized activities, 3-how the pursuit of these goals subordinates other activities. We account for such internalized activities by means of the sorts of interactive processes described by the interactivist model. They have a tendency, like that of Piaget schemes, to run cyclically, whenever possible. They are similar to real activities in that they draw on the same neural machinery, but their sensory-motor aspects are somehow inhibited. Not being enslaved to reality and its timing, they can run faster and in a discontinuous way. Multiple internalized processes may also co-occur with compatible sensory-motor operations, even though the latter are inhibited. When an activity is actually performed by an agent, we argue that a synchronization phenomenon makes previous similar activities run in an internalized way in parallel, and that they help to guide real activity by providing anticipated potentialities in real time. When we make a basketball shot, previous analogous shots run in internal synchrony at the same time, guiding the current attempt. A goal such as a successful shot can be initially present in the agent's mind as a persistent internalized activity. The tendency of internalized activities to run whenever possible allows for a sequence construction mechanism, which operates forward and backward, and permits the creation of sequences of internalized processes projecting from a current activity, such as dribbling against an opponent, to a goal activity, such as shooting. These ideas have been applied 1-to a computer program able to recognize musical rhythms by synchronizing actual rhythms to internalized ones, and 2-to the construction of a model of how an agent represents the routes it knows in a town and how these routes coordinate internally to produce sequences from a current location to a destination