Assessing the conformational changes of pb5, the receptor-binding protein of phage T5, upon binding to its Escherichia coli receptor FhuA

Within tailed bacteriophages, interaction of the receptor-binding protein (RBP) with the target cell triggers viral DNA ejection into the host cytoplasm. In the case of phage T5, the RBP pb5 and the receptor FhuA, an outer membrane protein of Escherichia coli, have been identified. Here, we use small angle neutron scattering and electron microscopy to investigate the FhuA-pb5 complex. Specific deuteration of one of the partners allows the complete masking in small angle neutron scattering of the surfactant and unlabeled proteins when the complex is solubilized in the fluorinated surfactant F6-DigluM. Thus, individual structures within a membrane protein complex can be described. The solution structure of FhuA agrees with its crystal structure; that of pb5 shows an elongated shape. Neither displays significant conformational changes upon interaction. The mechanism of signal transduction within phage T5 thus appears different from that of phages binding cell wall saccharides, for which structural information is available

[Introduction of Historical Material] The Draft of Fusan-ichiryu, Housed at Myohonji Main Temple of Awa

ここで紹介する史料は、文亀三年(一五〇三)七月二十五日に安房妙本寺の住職日要から「富山一流草案」を伝授された本寿坊日杲が天文二年(一五三三)七月七日に六位公日鎮に書写・授与したものである。妙本寺に伝来する日杲自筆本からの翻刻である

Complex interplay between β-catenin signalling and Notch effectors in intestinal tumorigenesis

International audienceAims The activation of β-catenin signalling is a key step in intestinal tumorigenesis. Interplay between the β-catenin and Notch pathways during tumorigenesis has been reported, but the mechanisms involved and the role of Notch remain unclear. Methods Notch status was analysed by studying expression of the Notch effector Hes1 and Notch ligands/receptors in human colorectal cancer (CRC) and mouse models of Apc mutation. A genetic approach was used, deleting the Apc and RBP-J or Atoh1 genes in murine intestine. CRC cell lines were used to analyse the control of Hes1 and Atoh1 by β-catenin signalling. Results Notch signalling was found to be activated downstream from β-catenin. It was rapidly induced and maintained throughout tumorigenesis. Hes1 induction was mediated by β-catenin and resulted from both the induction of the Notch ligand/receptor and Notch-independent control of the Hes1 promoter by β-catenin. Surprisingly, the strong phenotype of unrestricted proliferation and impaired differentiation induced by acute Apc deletion in the intestine was not rescued by conditional Notch inactivation. Hyperactivation of β-catenin signalling overrode the forced differention induced by Notch inhibition, through the downregulation of Atoh1, a key secretory determinant factor downstream of Notch. This process involves glycogen synthase kinase 3 β (GSK3β) and proteasome-mediated degradation. The restoration of Atoh1 expression in CRC cell lines displaying β-catenin activation was sufficient to increase goblet cell differentiation, whereas genetic ablation of Atoh1 greatly increased tumour formation in Apc mutant mice. Conclusion Notch signalling is a downstream target of β-catenin hyperactivation in intestinal tumorigenesis. However, its inhibition had no tumour suppressor effect in the context of acute β-catenin activation probably due to the downregulation of Atoh1. This finding calls into question the use of γ-secretase inhibitors for the treatment of CRC and suggests that the restoration of Atoh1 expression in CRC should be considered as a therapeutic approach

Nutrimetabolomics: An Integrative Action for Metabolomic Analyses in Human Nutritional Studies

The life sciences are currently being transformed by an unprecedented wave of developments in molecular analysis, which include important advances in instrumental analysis as well as biocomputing. In light of the central role played by metabolism in nutrition, metabolomics is rapidly being established as a key analytical tool in human nutritional studies. Consequently, an increasing number of nutritionists integrate metabolomics into their study designs. Within this dynamic landscape, the potential of nutritional metabolomics (nutrimetabolomics) to be translated into a science, which can impact on health policies, still needs to be realized. A key element to reach this goal is the ability of the research community to join, to collectively make the best use of the potential offered by nutritional metabolomics. This article, therefore, provides a methodological description of nutritional metabolomics that reflects on the state‐of‐the‐art techniques used in the laboratories of the Food Biomarker Alliance (funded by the European Joint Programming Initiative "A Healthy Diet for a Healthy Life" (JPI HDHL)) as well as points of reflections to harmonize this field. It is not intended to be exhaustive but rather to present a pragmatic guidance on metabolomic methodologies, providing readers with useful "tips and tricks" along the analytical workflow

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/)

La maison des Noces d'argent : entre idéal hellénistique et faste aristocratique

La culture grecque a fortement imprégné la culture romaine dès le IIe siècle avant notre ère. Se considérant comme un peuple rustique, paysan, les romains ont développé un certain « complexe d’infériorité » culturelle au sein d’une classe dirigeante opulente et oisive, désireuse de créer une atmosphère autour de valeurs refuges comme la famille, la fortune, l'art ou encore la philosophie. Par acculturation, est né un idéal imaginaire et pittoresque emprunt de théâtralité et de mise en scène d..

An algorithmic approach to characterizations of admissibles

International audienceSacks proved that every admissible countable ordinal is the first admissible ordinal relatively to a real. We give an algorithmic proof of this result for constructibly countable admissibles. Our study is completed by an algorithmic approach to a generalization of Sacks’ theorem due to Jensen, that finds a real relatively to which a countable sequence of admissibles, having a compatible structure, constitutes the sequence of the first admissibles. Our approach deeply involves infinite time Turing machines. We also present different considerations on the constructible ranks of the reals involved in coding ordinals

Le creusement d’un puits à l’époque amorrite

International audienc

Infinite Time Busy Beavers

International audienceIn 1962, Hungarian mathematician Tibor Radó introduced in [8] the busy beaver competition for Turing machines: in a class of machines, find one which halts after the greatest number of steps when started on the empty input. In this paper, we generalise the busy beaver competition to the infinite time Turing machines (ITTMs) introduced in [6] by Hamkins and Lewis in 2000. We introduce two busy beaver functions on ITTMs and show both theoretical and experimental results on these functions. We give in particular a comprehensive study, with champions for the busy beaver competition, of the classes of ITTMs with one or two states (in addition to the halt and limit states). The computation power of ITTMs is humongous and thus makes the experimental study of this generalisation of Radó’s competition and functions a daunting challenge. We end this paper with a characterisation of the power of those machines when the use of the tape is restricted in various ways

Synthèse, études physico-chimiques et biologiques de nouveaux spin traps amphiphiles

Les travaux décrits dans cette thèse ont pour objectifs la synthèse et les études physico-chimiques ainsi que biologiques de nouveaux spin traps amphiphiles dérivés de l'a-phenyl-N-tert-butylnitrone (PBN). Le caractère amphiphile de ces molécules est destiné à leur assurer une meilleure pénétration transmembranaire et par conséquent une meilleure protection cellulaire vis-à-vis des radicaux libres produits de manière naturelle et/ou accidentelle. Les activités antiradicalaires de ces nouveaux composés ont pu être confirmées sur divers modèles d'études et font de ces composés des agents protecteurs potentiellement utilisables dans des applications thérapeutiquesThe works described here, have been focused on the synthesis, the physico-chemical and the biological studies of a novel series of a-phenyl-N-tert-butylnitrone (PBN) derived amphiphilic spin-traps. The amphiphilic character of these compounds was supposed to enhance their membrane-crossing ability and thus to provide a better cellular protection against free radicals. The spin-trapping efficacy of these compounds has been specified by different experimental assays (ESR studies and in vitro biological models). Such new compounds should play a crucial role for the treatment of various diseases involving a free radicals generationAVIGNON-BU Centrale (840072102) / SudocSudocFranceF