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Acinetobacter baumannii, a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat and constitutes a growing threat to human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms is essential for addressing this critical medical need. Herein, we describe our efforts to inhibit the essential A. baumanniilipooligosaccharide (LOS) ATP-binding cassette (ABC) transporter MsbA. An unexpected impurity from a phenotypic screening was optimized as a series of dimeric compounds, culminating with 1(cerastecin D), which exhibited antibacterial activity in the presence of human serum and a pharmacokinetic profile sufficient to achieve efficacy against A. baumanniiin murine septicemia and lung infection models.

With the emergence of challenges in the environmental degradation and resource scarcity fields, the research of biobased self-healing polyurethane (BSPU) has become a prevailing trend in the technology of the polyurethane industry and a promising direction for developing biomass resources. Here, the production of BSPU from lignocellulose, vegetable oil, chitosan, collagen, and coumarin is classified, and the principles of designing polyurethane based on compelling examples using the latest methods and current research are summarized. Moreover, the impact of biomass materials on self-healing and mechanical properties, as well as the tailored performance method, are presented in detail. Finally, the applications of BSPU in biomedicine, sensors, coatings, etc. are also summarized, and the possible challenges and development prospects are explored to helpfully make progress in the development of BSPU. These findings demonstrate valuable references and practical significance for future BSPU research.

Cellulose nanocrystal (CNC)-based chiral nematic structure is widely used in stimulus response and sensing. A popular area of research is enhancing the mechanical characteristics and environmental adaptability of chiral nematic materials. In this paper, a flexible photonic film with self-healing ability (FPFS) was prepared by combining waterborne polyurethane containing dynamic covalent disulfide bonds (SSWPU) with CNC. The results found that the FPFS showed excellent toughness under the action of stretching, bending, twisting, and folding. The FPFS exhibited an amazing self-healing efficiency, which can be self-healed within 2 h at room temperature. Moreover, the FPFS could respond immediately and produce reversible color change when it was soaked in typical solvents. In addition, when ethanol was used as ink to paint on the FPFS, a visible pattern only under polarized light was formed. This study offers fresh perspectives in the areas of self-healing, biological anticounterfeiting, solvent response, and flexible photonic materials.

Au-delà d’un système de drainage, les voies lacrymales assurent une défense active de l’œil par l’action de la pompe lacrymale, la présence de la flore résidente (lacriome), et le tissu immunitaire associé aux muqueuses. L’infection survient lorsque les fonctions muqueuses immunitaires sont dépassées. L’infection lacrymale est un cercle vicieux, dans lequel l’infection entraîne inflammation et séquelles postinflammatoires, elles-mêmes source d’occlusion et de stagnation qui à leur tour font le lit de l’infection. Quel que soit le déclenchement initial : occlusion post-traumatique, inflammation par exemple allergique ou infestation par un germe virulent, la prise en charge de l’infection lacrymale doit tenir compte de ce cercle vicieux. Lorsque l’infection s’installe, les modifications de la muqueuse peuvent aller de l’infiltrat inflammatoire sous-muqueux aux pseudokystes, et dans les cas les plus sévères à la métaplasie, la dysplasie et le carcinome épidermoïde. Ainsi le prélèvement histologique est impératif en cas de chirurgie sur une muqueuse ayant subi une infection chronique. Le bilan clinique aidé au besoin du dacryoscanner, doit dépister les diagnostics différentiels (carcinome du sac, dacryocystocèle de l’enfant) et les formes graves (ophtalmie néonatale à gonocoque, péridacryocystite), rechercher les signes de présence de dacryolithes, et différencier infection aiguë et infection chronique. L’antibiothérapie doit être adaptée au germe en cause, identifié ou présumé, ou au contraire utilisée avec parcimonie en cas d’infection chronique. L’extraction des dacryolithes peut se faire par curage en cas de canaliculite à concrétions, mais nécessite une chirurgie pour les dacryolithes plus volumineux (canaliculotomie, ou dacryocystorhinostomie en cas de dacryolithe du sac). Enfin, l’antibioprophylaxie en chirurgie lacrymale est uniquement recommandée en cas de rhinosinusite associée, chez les patients avec inflammation du sac, ou chez des patients avec des antécédents de mucocèle infectée ou de dacryocystite.

AbstractWe consider a continuous Gaussian random field living on a compact set $T\subset \mathbb{R}^{d}$ . We are interested in designing an asymptotically efficient estimator of the probability that the integral of the exponential of the Gaussian process over Texceeds a large threshold u. We propose an Asmussen–Kroese conditional Monte Carlo type estimator and discuss its asymptotic properties according to the assumptions on the first and second moments of the Gaussian random field. We also provide a simulation study to illustrate its effectiveness and compare its performance with the importance sampling type estimator of Liu and Xu (2014a).

AbstractConditional mean risk sharing appears to be effective to distribute total losses amongst participants within an insurance pool. This paper develops analytical results for this allocation rule in the individual risk model with dependence induced by the respective position within a graph. Precisely, losses are modelled by zero-augmented random variables whose joint occurrence distribution and individual claim amount distributions are based on network structures and can be characterised by graphical models. The Ising model is adopted for occurrences and loss amounts obey decomposable graphical models that are specific to each participant. Two graphical structures are thus used: the first one to describe the contagion amongst member units within the insurance pool and the second one to model the spread of losses inside each participating unit. The proposed individual risk model is typically useful for modelling operational risks, catastrophic risks or cybersecurity risks.

Denuit (2019, 2020a) demonstrated that conditional mean risk sharing introduced by Denuit and Dhaene (2012) is the appropriate theoretical tool to share losses in collaborative peer-to-peer insurance schemes. Denuit and Robert (2020a, 2020b, 2021) studied this risk sharing mechanism and established several attractive properties including linear approximations when total losses or the number of participants get large. It is also shown there that the conditional expectation defining the conditional mean risk sharing is asymptotically increasing in the total loss (under mild technical assumptions). This ensures that the risk exchange is Pareto-optimal and that all participants have an interest to keep total losses as small as possible. In this article, we design a flexible system where entry prices can be made attractive compared to the premium of a regular, commercial insurance contract and participants are awarded cash-backs in case of favorable experience while being protected by a stop-loss treaty in the opposite case. Members can also be grouped according to some meaningful criteria, resulting in a hierarchical decomposition of the community. The particular case where realized losses are allocated in proportion to the pure premiums is studied.

In this study, we determined the crystal structure of an engineered human adenosine A2Areceptor bound to a partial agonist and compared it to structures cocrystallized with either a full agonist or an antagonist/inverse agonist. The interaction between the partial agonist, belonging to a class of dicyanopyridines, and amino acids in the ligand binding pocket inspired us to develop a small library of derivatives and assess their affinity in radioligand binding studies and potency and intrinsic activity in a functional, label-free, intact cell assay. It appeared that some of the derivatives retained the partial agonist profile, whereas other ligands turned into inverse agonists. We rationalized this remarkable behavior with additional computational docking studies.

Première cause d’épiphora congénital, l’imperméabilité du canal lacrymonasal (CLN) simple touche 5 à 20 % des nouveaux nés. Chez les enfants de plus de 12 mois, il est actuellement recommandé de procéder à un sondage avec intubation de la voie lacrymale sous anesthésie générale. Le but de cette étude est de comparer les sondes monocanaliculaires « tirées » type Monoka versus les sondes monocanaliculaires « poussées » type Masterka.

To evaluate the applicability of anterior segment optical coherence tomography (AS-OCT) for objective diagnosis of punctal stenosis.

All-solid-state lithium metal batteries are highly attractive because of their high energy density and inherent safety. However, it is still a great challenge to design the solid electrolytes with high ionic conductivity at room temperature and good electrode/electrolyte interfacial compatibility simultaneously in a facile and scalable way. In this work, for the first time, the combination of salt affluent Poly(ethylene oxide) with Li6.75La3Zr1.75Ta0.25O12nanofibers was designed and intensively evaluated. The synergistic effect of each component in the electrolyte enhances the ionic conductivity to 2.13 × 10–4S cm–1at 25 °C and exhibits a high transference number of 0.57. The composite electrolyte possesses superior interfacial stability against Li metal for over 680 h in Li symmetric cells even at a relatively high current density of 2 mA cm–2. The all-solid-state batteries employing the solid electrolytes exhibit excellent cycling stability at room temperature and superior safety performance. This work proposes a brand-new strategy to design and fabricate solid electrolytes in a versatile way for room-temperature all-solid-state batteries.

This paper considers risk-sharing schemes, aiming to demonstrate that it is possible to enforce equal compensations by charging actuarially fair contributions. Specifically, consider a group of individuals exposed to the occurrence of a predefined event with adverse financial consequences such as death, survival or being diagnosed with a critical illness for instance. All members of the group agree to contribute in advance a fixed amount to a pool constituted over a reference period with the understanding that the sum of the contributions is shared in arrear among those participants having experienced the predefined event. This allocation is either uniform among claiming participants, each one receiving an equal share of total contributions, or participants are offered the choice to select a desired protection level. In the latter case, participants are free to subscribe one or several units of protection from the fund, and the total amount collected in advance is shared in arrear, equally among all units held by those participants who experienced the predefined event. Endowment contingency funds aim to provide participants with a cheap and effective protection compared to commercial insurance. The reason is that the proposed system is fully funded so that there is no risk borne by the organizer. The benefits in case the event occurs are therefore random but the volatility of the terminal payouts turns out to be limited when the number of participants gets large enough. Under independence, insurance at fair price is recovered at the limit, within infinitely large pools. As an application, the paper considers mutual aid funds and survivor funds. A comparison with takaful insurance is performed.

The purpose of this study was to compare the safety and efficacy of a new cationic emulsion (CE) with a formulation of polyvinyl alcohol and povidone (PVA-P) for the treatment of mild to moderate dry eye disease.

The purpose of this study is to analyse the 2-stage Müller's muscle flap technique for the treatment of orbital implant exposure and its results.

Implant exposure is the most frequent complication after evisceration or enucleation, and multiple surgical techniques for implantation have been described. The goal of our study is to investigate the success rate and risk factors for failure of various surgical procedures.

But: Cet essai clinique de phase III, comparatif, randomisé, multicentrique en double insu, avait pour but de montrer la supériorité des injections sous-conjonctivales de Bévacizumab contre placebo dans le traitement de la néovascularisation cornéenne.

Interface engineering has been recognized to be substantially critical for achieving efficient charge separation, charge carrier transport, and enhanced device performance in emerging optoelectronics. Nevertheless, precise control of the interface structure using current techniques remains a formidable challenge. Herein, we demonstrate a facile and versatile protocol wherein in situ thiol–ene click photopolymerization-induced phase separation is implemented for constructing heterojunction semiconductor interfaces. This approach generates continuous mountainlike heterojunction interfaces that favor efficient exciton dissociation at the interface while providing a continuous conductive area for hole transport above the interface. This facile low-temperature paradigm presents good adaptability to both rigid and flexible substrates, offering high-performance UV-responsive phototransistors with a normalized detectivity up to 6.3 × 1014cm Hz1/2W–1(also called jones). Control experiments based on ex situ photopolymerization and in situ thermal polymerization are also implemented to demonstrate the superiority of this novel paradigm.

Piezoresistive microsensors are considered to be essential components of the future wearable electronic devices. However, the expensive cost, complex fabrication technology, poor stability, and low yield have limited their developments for practical applications. Here, we present a cost-effective, relatively simple, and high-yield fabrication approach to construct highly sensitive and ultrastable piezoresistive sensors using a bioinspired hierarchically structured graphite/polydimethylsiloxane composite as the active layer. In this fabrication, a commercially available sandpaper is employed as the mold to develop the hierarchical structure. Our devices exhibit fascinating performance including an ultrahigh sensitivity (64.3 kPa–1), fast response time (<8 ms), low limit of detection of 0.9 Pa, long-term durability (>100 000 cycles), and high ambient stability (>1 year). The applications of these devices in sensing radial artery pulses, acoustic vibrations, and human body motion are demonstrated, exhibiting their enormous potential use in real-time healthcare monitoring and robotic tactile sensing.

Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation. PARs have been the subject of major pharmaceutical research efforts but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses.

Previous investigations on rare-earth oxides (REOs) reveal their high possibility as dielectric films in electronic devices, while complicated physical methods impede their developments and applications. Herein, we report a facile route to fabricate 16 REOs thin insulating films through a general solution process and their applications in low-voltage thin-film transistors as dielectrics. The formation and properties of REOs thin films are analyzed by atomic force microscopy (AFM), X-ray diffraction (XRD), spectroscopic ellipsometry, water contact angle measurement, X-ray photoemission spectroscopy (XPS), and electrical characterizations, respectively. Ultrasmooth, amorphous, and hydrophilic REO films with thickness around 10 nm have been obtained through a combined spin-coating and postannealing method. The compositional analysis results reveal the formation of RE hydrocarbonates on the surface and silicates at the interface of REOs films annealed on Si substrate. The dielectric properties of REO films are investigated by characterizing capacitors with a Si/Ln2O3/Au (Ln = La, Gd, and Er) structure. The observed low leakage current densities and large areal capacitances indicate these REO films can be employed as alternative gate dielectrics in transistors. Thus, we have successfully fabricated a series of low-voltage organic thin-film transistors based on such sol–gel derived REO films to demonstrate their application in electronics. The optimization of REOs dielectrics in transistors through further surface modification has also been studied. The current study provides a simple solution process approach to fabricate varieties of REOs insulating films, and the results reveal their promising applications as alternative gate dielectrics in thin-film transistors.

Field‐effect transistors (FETs) employing the solution‐processed metal oxides as dielectrics have shown excellent performance on rigid silicon substrate. However, there have been very limited reports on FETs with solution‐processed, thermal‐annealed metal oxide dielectrics on low‐cost flexible substrates. To date, to our knowledge there is almost no report on flexible FETs having the similar or better performance than the FETs on Si substrate with solution‐processed, thermal‐annealed metal oxides as dielectrics. Herein, flexible pentacene‐based organic FETs have been demonstrated with polystyrene (PS)‐modified, solution‐processed yttrium oxide (Y2O3), hafnium oxide (HfO2), or aluminum oxide (Al2O3) as dielectrics on commercially available aluminum (Al) foil substrates. The transistors exhibit a good carrier mobility (µ), a large on/off current ratio (Ion/off), a low threshold voltage (VT), and a small subthreshold swing (SS) at a low‐operation voltage (−4 V), which is comparable with the device performance on rigid Si substrate. Therefore, the excellent electrical performance of the FETs on commercially available Al foil substrate, together with the virtue of light‐weight, makes the devices possess the promising potential for various electronic system applications.

L’apparition de vaisseaux sanguins au sein du stroma cornéen normalement avasculaire définit la néovascularisation cornéenne. Si ses aspects physiopathologiques et cliniques sont connus de longue date, ses modalités thérapeutiques ont longtemps souffert du manque de traitements efficaces et restent encore aujourd’hui controversées. Nous présentons dans cette revue de la littérature les différentes options thérapeutiques à la lumière des récentes études chez l’homme et l’animal. La première partie détaille les traitements pharmacologiques en précisant plus particulièrement l’action des molécules anti-angiogéniques. Le bévacizumab utilisé par voie topique ou par injections sous-conjonctivales a ainsi fait la preuve de son efficacité sur la réduction de la néovascularisation cornéenne. Son faible coût et sa sécurité d’emploi en font actuellement la molécule anti-angiogénique de choix. Néanmoins, le développement récent de thérapeutiques anti-angiogéniques ciblant les voies intracellulaires de l’angiogenèse (SiRNA, oligonucléotides anti-sens) constitue une alternative prometteuse. Les traitements par laser (photocoagulation directe ou dynamique) et l’électrocoagulation à l’aiguille fine des néovaisseaux trouvent leurs places dans le traitement des formes stabilisées d’angiogenèse cornéenne seuls ou en association avec les traitements anti-angiogéniques. La reconstruction de la surface oculaire par greffe de membrane amniotique ou greffe de cellules souches limbiques revêt un intérêt capital lorsque la néovascularisation cornéenne survient dans les suites d’une insuffisance limbique primitive ou acquise.

Les syndromes inflammatoires orbitaires regroupent une grande variété de processus intraorbitaires d’aspect inflammatoire très différents dans leurs présentations cliniques et leurs pronostics. On préfère actuellement différencier les inflammations orbitaires, dites spécifiques, pour lesquelles une étiologie a pu être identifiée, des syndromes inflammatoires orbitaires idiopathiques (SIOI) pour lesquelles l’étiologie reste inconnue et l’histologie non spécifique.

Asymptotic expansions for the tails of sums of random variables with regularly varying tails are mainly derived in the case of identically distributed random variables or in the case of random variables with the same tail index. Moreover, the higher-order terms are often given under the condition of existence of a moment of the distribution. In this paper, we obtain infinite series expansions for convolutions of Pareto distributions with non-integer tail indices. The Pareto random variables may have different tail indices and different scale parameters. We naturally find the same constants for the first terms as given in the previous asymptotic expansions in the case of identically distributed random variables, but we are now able to give the next additional terms. Since our series expansion is not asymptotic, it may be also used to compute the values of quantiles of the distribution of the sum as well as other risk measures such as the Tail Value at Risk. Examples of values are provided for the sum of at least five Pareto random variables and are compared to those determined via previous asymptotic expansions or via simulations.

In ruin theory, the conjecture given in De Vylder and Goovaerts (2000) is an open problem about the comparison of the finite time ruin probability in a homogeneous risk model and the corresponding ruin probability evaluated in the associated model with equalized claim amounts. In this paper we consider a weaker version of the conjecture and show that the integrals of the ruin probabilities with respect to the initial risk reserve are uniformly comparable.