Nonreciprocal synchronization in embryonic oscillator ensembles.

Synchronization of coupled oscillators is a universal phenomenon encountered across different scales and contexts, e.g., chemical wave patterns, superconductors, and the unison applause we witness in concert halls. The existence of common underlying coupling rules defines universality classes, revealing a fundamental sameness between seemingly distinct systems. Identifying rules of synchronization in any particular setting is hence of paramount relevance. Here, we address the coupling rules within an embryonic oscillator ensemble linked to vertebrate embryo body axis segmentation. In vertebrates, the periodic segmentation of the body axis involves synchronized signaling oscillations in cells within the presomitic mesoderm (PSM), from which somites, the prevertebrae, form. At the molecular level, it is known that intact Notch-signaling and cell-to-cell contact are required for synchronization between PSM cells. However, an understanding of the coupling rules is still lacking. To identify these, we develop an experimental assay that enables direct quantification of synchronization dynamics within mixtures of oscillating cell ensembles, for which the initial input frequency and phase distribution are known. Our results reveal a "winner-takes-it-all" synchronization outcome, i.e., the emerging collective rhythm matches one of the input rhythms. Using a combination of theory and experimental validation, we develop a coupling model, the "Rectified Kuramoto" (ReKu) model, characterized by a phase-dependent, nonreciprocal interaction in the coupling of oscillatory cells. Such nonreciprocal synchronization rules reveal fundamental similarities between embryonic oscillators and a class of collective behaviors seen in neurons and fireflies, where higher-level computations are performed and linked to nonreciprocal synchronization.

Impact of targeted hypothermia in expanded-criteria organ donors on recipient kidney-graft function: study protocol for a multicentre randomised controlled trial (HYPOREME).

INTRODUCTION: Expanded-criteria donors (ECDs) are used to reduce the shortage of kidneys for transplantation. However, kidneys from ECDs are associated with an increased risk of delayed graft function (DGF), a risk factor for allograft loss and mortality. HYPOREME will be a multicentre randomised controlled trial (RCT) comparing targeted hypothermia to normothermia in ECDs, in a country where the use of machine perfusion for organ storage is the standard of care. We hypothesise that hypothermia will decrease the incidence of DGF. METHODS AND ANALYSIS: HYPOREME is a multicentre RCT comparing the effect on kidney function in recipients of targeted hypothermia (34°C-35°C) and normothermia (36.5°C-37.5°C) in the ECDs. The temperature intervention starts from randomisation and is maintained until aortic clamping in the operating room. We aim to enrol 289 ECDs in order to analyse the kidney function of 516 recipients in the 53 participating centres. The primary outcome is the occurrence of DGF in kidney recipients, defined as a requirement for renal replacement therapy within 7 days after transplantation (not counting a single session for hyperkalemia during the first 24 hours). Secondary outcomes include the proportion of patients with individual organs transplanted in each group; the number of organs transplanted from each ECD and the vital status and kidney function of the recipients 7 days, 28 days, 3 months and 1 year after transplantation. An interim analysis is planned after the enrolment of 258 kidney recipients. ETHICS AND DISSEMINATION: The trial was approved by the ethics committee of the French Intensive Care Society (CE-SRLF-16-07) on 26 April 2016 and by the competent French authorities on 20 April 2016 (Comité de Protection des Personnes-TOURS-Région Centre-Ouest 1, registration #2016-S3). Findings will be published in peer-reviewed journals and presented during national and international scientific meetings. TRIAL REGISTRATION NUMBER: NCT03098706.

Specialized Pro-Resolving Mediators Derived from N-3 Polyunsaturated Fatty Acids: Role in Metabolic Syndrome and Related Complications.

Significance: Metabolic syndrome (MetS) prevalence continues to grow and represents a serious public health issue worldwide. This multifactorial condition carries the risk of hastening the development of type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). Another troubling aspect of MetS is the requirement of poly-pharmacological therapy not devoid of side effects. Therefore, there is an urgent need for prospecting alternative nutraceuticals as effective therapeutic agents for MetS. Recent Advances: Currently, there is an increased interest in understanding the regulation of metabolic derangements by specialized pro-resolving lipid mediators (SPMs), especially those derived from the long chain n-3 polyunsaturated fatty acids. Critical Issues: The SPMs are recognized as efficient modulators that are capable of inhibiting the production of pro-inflammatory cytokines, blocking neutrophil activation/recruitment, and inducing non-phlogistic (anti-inflammatory) activation of macrophage engulfment and removal of apoptotic inflammatory cells and debris. The aim of the present review is precisely to first underline key concepts relative to SPM functions before focusing on their status and actions on MetS components (e.g., obesity, glucose dysmetabolism, hyperlipidemia, hypertension) and complications such as T2D, NAFLD, and CVD. Future Directions: Valuable data from preclinical and clinical investigations have emphasized the SPM functions and influence on oxidative stress- and inflammation-related MetS. Despite these promising findings obtained without compromising host defense, additional efforts are needed to evaluate their potential therapeutic applications and further develop practical tools to monitor their bioavailability to cope with cardiometabolic disorders. Antioxid. Redox Signal. 37, 54-83.

Geometric models for robust encoding of dynamical information into embryonic patterns.

During development, cells gradually assume specialized fates via changes of transcriptional dynamics, sometimes even within the same developmental stage. For anterior-posterior (AP) patterning in metazoans, it has been suggested that the gradual transition from a dynamic genetic regime to a static one is encoded by different transcriptional modules. In that case, the static regime has an essential role in pattern formation in addition to its maintenance function. In this work, we introduce a geometric approach to study such transition. We exhibit two types of genetic regime transitions arising through local or global bifurcations, respectively. We find that the global bifurcation type is more generic, more robust, and better preserves dynamical information. This could parsimoniously explain common features of metazoan segmentation, such as changes of periods leading to waves of gene expressions, 'speed/frequency-gradient' dynamics, and changes of wave patterns. Geometric approaches appear as possible alternatives to gene regulatory networks to understand development.

Modelling Time-Dependent Acquisition of Positional Information.

Theoretical and computational modelling are crucial to understand dynamics of embryonic development. In this tutorial chapter, we describe two models of gene networks performing time-dependent acquisition of positional information under control of a dynamic morphogen: a toy-model of a bistable gene under control of a morphogen, allowing for the numerical computation of a simple Waddington's epigenetic landscape, and a recently published model of gap genes in Tribolium under control of multiple enhancers. We present detailed commented implementations of the models using python and jupyter notebooks.

Transplantation of kidneys from uncontrolled donation after circulatory determination of death: comparison with brain death donors with or without extended criteria and impact of normothermic regional perfusion.

The aim of this study was to compare the outcomes of kidney transplants from uncontrolled DCD (uDCD) with kidney transplants from extended (ECD) and standard criteria donors (SCD). In this multicenter study, we included recipients from uDCD (n = 50), and from ECD (n = 57) and SCD (n = 102) who could be eligible for a uDCD program. We compared patient and graft survival, and kidney function between groups. To address the impact of preservation procedures in uDCD, we compared in situ cold perfusion (ICP) with normothermic regional perfusion (NRP). Patient and graft survival rates were similar between the uDCD and ECD groups, but were lower than the SCD group (P < 0.01). Although delayed graft function (DGF) was more frequent in the uDCD group (66%) than in the ECD (40%) and SCD (27%) groups (P = 0.08 and P < 0.001), graft function was comparable between the uDCD and ECD groups at 3 months onwards post-transplantation. The use of NRP in the uDCD group (n = 19) was associated with a lower risk of DGF, and with a better graft function at 2 years post-transplantation, compared to ICP-uDCD (n = 31) and ECD. In conclusion, the use of uDCD kidneys was associated with post-transplantation results comparable to those of ECD kidneys. NRP preservation may improve the results of uDCD transplantation.

Interest of low-dose hydrocortisone therapy during brain-dead organ donor resuscitation: the CORTICOME study.

INTRODUCTION: Circulatory failure during brain death organ donor resuscitation is a problem that compromises recovery of organs. Combined administration of steroid, thyroxine and vasopressin has been proposed to optimize the management of brain deceased donors before recovery of organs. However the single administration of hydrocortisone has not been rigorously evaluated in any trial. METHODS: In this prospective multicenter cluster study, 259 subjects were included. Administration of low-dose steroids composed the steroid group (n = 102). RESULTS: Although there were more patients in the steroid group who received norepinephrine before brain death (80% vs. 66%: P = 0.03), mean dose of vasopressor administered after brain death was significantly lower than in the control group (1.18 ± 0.92 mg/H vs. 1.49 ± 1.29 mg/H: P = 0.03), duration of vasopressor support use was shorter (874 min vs. 1160 min: P < 0.0001) and norepinephrine weaning before aortic clamping was more frequent (33.8% vs. 9.5%: P < 0.0001). Using a survival approach, probability of norepinephrine weaning was significantly different between the two groups (P < 0.0001) with a probability of weaning 4.67 times higher in the steroid group than in the control group (95% CI: 2.30 - 9.49). CONCLUSIONS: Despite no observed benefits of the steroid administration on primary function recovery of transplanted grafts, administration of glucocorticoids should be a part of the resuscitation management of deceased donors with hemodynamic instability.

Impact of screening and identifying methicillin-resistant Staphylococcus aureus carriers on hand hygiene compliance in 4 intensive care units.

BACKGROUND: Our objective was to assess the impact of screening and identifying methicillin-resistant Staphylococcus aureus (MRSA) carriers as a single measure in 4 intensive care units (ICUs). METHODS: An evaluative study including two 6-month periods was conducted prospectively. The evaluation concerned the hand hygiene compliance (HHC) for contacts with MRSA carriers versus contacts with noncarriers (comparison C1, main objective) and for a period of absence of identification (P1) versus a period of identification (P2) (comparison C2) and MRSA cross transmission (P1 vs P2) (comparison C3) measured with 2 indicators. RESULTS: Overall, 1326 opportunities of hand hygiene were observed. Concerning C1, the HHC for contacts with MRSA carriers was 42.5% versus 43.1% for contacts with noncarriers (not significant). This absence of difference was recorded whatever the ICU specialty, the category of personnel, and the nature of contacts. Concerning C2, the HHC in P1 was 44.8% versus 48.5% in P2 (not significant). Concerning C3, no significant difference was identified between the 2 periods. CONCLUSION: We did not identify any advantage by using screening and identifying MRSA carriers in those 4 ICUs in which no specific strategy of additional contact measures was implemented for MRSA carriers.

In vivo efficacy of linezolid in combination with gentamicin for the treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus.

Indifference or even antagonism has mainly been reported with combinations including linezolid. The presence of in vitro antagonism is not always correlated with in vivo failure. The purpose of this study was to evaluate the in vivo activity of linezolid combined with gentamicin using a methicillin-resistant Staphylococcus aureus (MRSA) endocarditis experimental model. A human-like pharmacokinetic simulation was used for linezolid and gentamicin to improve the extrapolation of the results to human therapy. Contrary to the antagonism previously described in vitro, linezolid combined with gentamicin exhibited bactericidal activity on the two strains with a decrease of at least 4 log(10)cfu/g of vegetation compared with controls. These data suggest that linezolid plus gentamicin could be an appropriate combination for the treatment of severe MRSA infections.