PNIPAM grafted surfaces through ATRP and RAFT polymerization: Chemistry and bioadhesion

Biomaterials surface design is critical for the control of materials and biological system interactions.Being regulated by a layer of molecular dimensions, bioadhesion could be effectively tailored by polymersurface grafting. Basically, this surface modification can be controlled by radical polymerization, whichis a useful tool for this purpose. The aim of this review is to provide a comprehensive overview of therole of surface characteristics on bioadhesion properties. We place a particular focus on biomaterialsfunctionalized with a brush surface, on presentation of grafting techniques for “grafting to” and “graft-ing from” strategies and on brush characterization methods. Since atom transfer radical polymerization(ATRP) and reversible addition-fragmentation chain transfer (RAFT) polymerization are the most fre-quently used grafting techniques, their main characteristics will be explained. Through the example ofpoly(N-isopropylacrylamide) (PNIPAM) which is a widely used polymer allowing tuneable cell adhesion,smart surfaces involving PNIPAM will be presented with their main modern applications

Time course, factors related to, and prognostic impact of venoarterial extracorporeal membrane flow in cardiogenic shock

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is currently one of the most used devices in refractory cardiogenic shock. However, there is a lack of evidence on how to set the 'optimal' flow. We aimed to describe the evolution of VA-ECMO flows in a cardiogenic shock population and determine the risk factors of 'high-ECMO flow'. A 7 year database of patients supported with VA-ECMO was used. Based on the median flow during the first 48 h of the VA-ECMO run, patients were classified as 'high-flow' or 'low-flow', respectively, when median ECMO flow was ≥3.6 or <3.6 L/min. Outcomes included rates of ventilator-associated pneumonia, ECMO-related complications, days on ECMO, days on mechanical ventilation, intensive care unit and hospitalization lengths of stay, and in-hospital and 60 day mortality. Risk factors of high-ECMO flow were assessed using univariate and multivariate cox regression. The study population included 209 patients on VA-ECMO, median age was 51 (40-59) years, and 78% were males. The most frequent aetiology leading to cardiogenic shock was end-stage dilated cardiomyopathy (57%), followed by acute myocardial infarction (23%) and fulminant myocarditis (17%). Among the 209 patients, 105 (50%) were classified as 'high-flow'. This group had a higher rate of ischaemic aetiology (16% vs. 30%, P = 0.023) and was sicker at admission, in terms of worse Simplified Acute Physiology Score II score [40 (26-58) vs. 56 (42-74), P < 0.001], higher lactate [3.6 (2.2-5.8) mmol/L vs. 5.2 (3-9.7) mmol/L, P < 0.001], and higher aspartate aminotransferase [97 (41-375) U/L vs. 309 (85-939) U/L, P < 0.001], among others. The 'low-flow' group had less ventilator-associated pneumonia (40% vs. 59%, P = 0.007) and less days on mechanical ventilation [4 (1.5-7.5) vs. 6 (3-12) days, P = 0.009]. No differences were found in lengths of stay or survival according to the ECMO flow. The multivariate analysis showed that risk factors independently associated with 'high-flow' were mechanical ventilation at cannulation [odds ratio (OR) 3.9, 95% confidence interval (CI) 2.1-7.1] and pre-ECMO lactate (OR 1.1, 95% CI 1.0-1.2). In patients with refractory cardiogenic shock supported with VA-ECMO, sicker patients had higher support since early phases, presenting thereafter higher rates of ventilator-associated pneumonia but similar survival compared with patients with lower flows

Mps1 Phosphorylates Its N-Terminal Extension to Relieve Autoinhibition and Activate the Spindle Assembly Checkpoint

Monopolar spindle 1 (Mps1) is a conserved apical kinase in the spindle assembly checkpoint (SAC) that ensures accurate segregation of chromosomes during mitosis. Mps1 undergoes extensive auto- and transphosphorylation, but the regulatory and functional consequences of these modifications remain unclear. Recent findings highlight the importance of intermolecular interactions between the N-terminal extension (NTE) of Mps1 and the Hec1 subunit of the NDC80 complex, which control Mps1 localization at kinetochores and activation of the SAC. Whether the NTE regulates other mitotic functions of Mps1 remains unknown. Here, we report that phosphorylation within the NTE contributes to Mps1 activation through relief of catalytic autoinhibition that is mediated by the NTE itself. Moreover, we find that this regulatory NTE function is independent of its role in Mps1 kinetochore recruitment. We demonstrate that the NTE autoinhibitory mechanism impinges most strongly on Mps1-dependent SAC functions and propose that Mps1 activation likely occurs sequentially through dimerization of a “prone-to-autophosphorylate” Mps1 conformer followed by autophosphorylation of the NTE prior to maximal kinase activation segment trans-autophosphorylation. Our observations underline the importance of autoregulated Mps1 activity in generation and maintenance of a robust SAC in human cells

Sea ice diatom contributions to Holocene nutrient utilization in East Antarctica

Combined high-resolution Holocene δ30Sidiat and δ13Cdiat paleorecords are presented from theSeasonal Ice Zone, East Antarctica. Both data sets reflect periods of increased nutrient utilization by diatomsduring the Hypsithermal period (circa 7800 to 3500 calendar years (cal years) B.P.), coincident with a higherabundance of open water diatom species (Fragilariopsis kerguelensis), increased biogenic silica productivity(%BSi), and higher regional summer temperatures. The Neoglacial period (after circa 3500 cal years B.P.) isreflected by an increase in sea ice indicative species (Fragilariopsis curta and Fragilariopsis cylindrus,upto50%) along with a decrease in %BSi and δ13Cdiat(< 18‰ to 23‰). However, over this period, δ30Sidiatdata show an increasing trend, to some of the highest values in the Holocene record (average of +0.43‰).Competing hypotheses are discussed to account for the decoupling trend in utilization proxies including ironfertilization, species-dependent fractionation effects, and diatom habitats. Based on mass balance calculations,we highlight that diatom species derived from the semi-enclosed sea ice environment may have a confoundingeffect upon δ30Sidowncorecompositions of the seasonal sea ice zone. A diatom composition, with approximately28% of biogenic silica derived from the sea ice environment (diat-SI) can account for the increased averagecompo sition of δ30Sidiatduring the Neoglacial. These data highlight the significant role sea ice diatoms can playwith relation to their export in sediment records, which has implications on productivity reconstructions fromthe seasonal ice zone

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Serum levels of mitochondrial inhibitory factor 1 are independently associated with long-term prognosis in coronary artery disease: the GENES Study

Background Epidemiological and observational studies have established that high-density lipoprotein cholesterol (HDL-C) is an independent negative cardiovascular risk factor. However, simple measurement of HDL-C levels is no longer sufficient for cardiovascular risk assessment. Therefore, there is a critical need for novel non-invasive biomarkers that would display prognostic superiority over HDL-C. Cell surface ecto-F1-ATPase contributes to several athero-protective properties of HDL, including reverse cholesterol transport and vascular endothelial protection. Serum inhibitory factor 1 (IF1), an endogenous inhibitor of ecto-F1-ATPase, is an independent determinant of HDL-C associated with low risk of coronary artery disease (CAD). This work aimed to examine the predictive value of serum IF1 for long-term mortality in CAD patients. Its informative value was compared to that of HDL-C. Method Serum IF1 levels were measured in 577 male participants with stable CAD (age 45–74 years) from the GENES (Genetique et ENvironnement en Europe du Sud) study. Vital status was yearly assessed, with a median follow-up of 11 years and a 29.5 % mortality rate. Cardiovascular mortality accounted for the majority (62.4 %) of deaths. Results IF1 levels were positively correlated with HDL-C (rs = 0.40; P < 0.001) and negatively with triglycerides (rs = −0.21, P < 0.001) and CAD severity documented by the Gensini score (rs = −0.13; P < 0.01). Total and cardiovascular mortality were lower at the highest quartiles of IF1 (HR = 0.55; 95 % CI, 0.38–0.89 and 0.50 (0.28–0.89), respectively) but not according to HDL-C. Inverse associations of IF1 with mortality remained significant, after multivariate adjustments for classical cardiovascular risk factors (age, smoking, physical activity, waist circumference, HDL-C, dyslipidemia, hypertension, and diabetes) and for powerful biological and clinical variables of prognosis, including heart rate, ankle-brachial index and biomarkers of cardiac diseases. The 10-year mortality was 28.5 % in patients with low IF1 (<0.42 mg/L) and 21.4 % in those with high IF1 (≥0.42 mg/L, P < 0.02). Conclusions We investigated for the first time the relation between IF1 levels and long-term prognosis in CAD patients, and found an independent negative association. IF1 measurement might be used as a novel HDL-related biomarker to better stratify risk in populations at high risk or in the setting of pharmacotherapy

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/)

Étude de l'extension N-terminale de la kinase mitotique MPS1

Une des premières caractéristiques reconnues dans les cellules cancéreuses fut l’observation d’aberrations chromosomiques au cours de la division cellulaire. Parmi ces aberrations, on retrouve l’aneuploïdie, une mutation génétique définie par un nombre de chromosomes anormal de la cellule. Première cause associée aux fausses couches et au retard mental, l’aneuploïdie participe également à la progression tumorale. Plusieurs mécanismes sont mis en place par la cellule pour parer à ces aberrations chromosomiques. Le « spindle assembly checkpoint » (SAC) fait partie de ces mécanismes qui assurent la ségrégation précise des chromosomes au cours de la mitose. La kinase à double spécificité MPS1 codée par le gène TTK est une composante critique du SAC. La régulation de l’activité et de la localisation de MPS1 reste encore incomprise dans son ensemble. La localisation de MPS1 aux kinétochores (KT, structure des centromères permettant la mise en place du SAC) nécessite une région d’environ 50 acides aminés appelée NTE (N-Terminal Extension) qui ne possède pas de domaine fonctionnel clairement défini. Des données récentes ont montré que la région N-Terminale de MPS1 est impliquée dans la régulation de son activité. L’objectif principal de ces travaux est de comprendre dans quelle mesure la région NTE participe à la régulation de l’activité kinase et à la localisation de MPS1. Mettant en place une approche basée sur l’hypothèse que la conservation de la structure à travers l’évolution peut correspondre à une fonction, nous avons mis en évidence que la région NTE de MPS1 contribue à sa localisation et son activation par 2 modules indépendants. Nous avons démontré que les résidus 19-29 sont absolument requis pour la localisation de MPS1 déterminant ainsi plus précisément une région responsable de sa localisation. Cette région est également nécessaire pour diminuer l’interaction entre MPS1 et sa protéine partenaire ARHGEF17/TEM4 qui participe à son recrutement au KT, régulant de ce fait la localisation de MPS1. Le second module concerne les résidus 40-49 et c’est en particulier la phosphorylation de cette région qui contribue à l’activation de la kinase, vraisemblablement par la relâche d’un mécanisme d’auto-inhibition de la kinase. Ce mécanisme, participant à la régulation de l’activité kinase de MPS1, semble se produire successivement avec la dimérisation, puis la phosphorylation initiale de la région NTE et est enfin suivie de la trans-autophosphorylation de la boucle d’activation du domaine kinase. L’importance de la région NTE dans l’accomplissement des fonctions de MPS1 au cours de la mitose a été démontrée ainsi que la nécessité de ces deux régions particulières de la NTE requises indépendamment pour le fonctionnement optimal et le maintien de la robustesse du SAC. Ainsi, cette thèse apporte des informations supplémentaires et indispensables à la compréhension des mécanismes régulant l’activité kinase et la localisation au kinétochore de MPS1 par l’intermédiaire de sa région NTE.One of the first recognized characteristics in cancer cells was the observation of chromosomal aberrations during cell division. Among these aberrations, there is aneuploidy, a genetic abnormality defined by having an incorrect number of chromosomes in the cell. As the leading cause of miscarriages and mental retardation, aneuploidy also contributes to tumor progression. Several mechanisms are established by the cell to counter these chromosomal aberrations. The "spindle assembly control point" (SAC) is one of these mechanisms which ensures accurate segregation of chromosomes during mitosis. The dual specificity kinase MPS1 coded by the TTK gene is a critical component of the SAC. The regulation of the activity and the localization of MPS1 is still not wholly understood. The localization of MPS1 to the kinetochores (KT, structure of the centromeres allowing SAC organization) requires a region of approximately 50 amino acids called NTE (N-Terminal Extension) which does not exhibit a known functional domain. Recent data have demonstrated that the N-Terminal region of MPS1 is involved in the regulation of its activity. The main objective of this project is to understand to what extent the NTE region participates in the regulation of the kinase activity and the localization of MPS1. Using a structure-based approach, we have demonstrated that the NTE region of MPS1 contributes to its localization and activation by 2 independent modules. We demonstrated that residues 19-29 are absolutely required for the localization of MPS1, thus defining more accurately the region responsible for its localization. This region is also necessary to decrease the interaction between MPS1 and its partner protein ARHGEF17/TEM4, which participates in its recruitment to the KT thereby regulating the localization of MPS1. The second module concerns the residues 40-49, especially the phosphorylation of this region which contributes to the activation of the kinase, presumably by the release of a mechanism of auto-inhibition of the kinase. This mechanism, which participates in the regulation of the MPS1 kinase activity, appears to occur successively with dimerization then the initial phosphorylation of the NTE region and finally followed by trans-autophosphorylation of the activation loop of the kinase domain. The importance of the NTE region in performing the functions of MPS1 during mitosis has been demonstrated as well as the need for these two particular regions of the NTE which are independently required for optimal functioning and maintaining the robustness of the SAC. Thus, this thesis provides additional and indispensable information for understanding the mechanisms regulating the kinase activity and the kinetochore localization of MPS1 via its NTE region