Immune therapies in pancreatic ductal adenocarcinoma: Where are we now?

Pancreatic ductal adenocarcinoma(PDAC)is one of the deadliest cancers,mostly due to its resistance to treatment.Of these,checkpoint inhibitors(CPI)are inefficient when used as monotherapy,except in the case of a rare subset of tumors harboring microsatellite instability(<2%).This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC.The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancerassociated-fibroblast activation and transforming growth factorβsecretion.Several strategies have recently been developed to overcome this immunosuppressive microenvironment.Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells.Ongoing studies are therefore exploring the association of CPI with vaccines,oncolytic viruses,MEK inhibitors,cytokine inhibitors,and hypoxia-and stroma-targeting agents.Adoptive T-cell transfer is also under investigation.Moreover,translational studies on tumor tissue and blood,prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.

Mass spectrometry detection of basic drugs in fast chiral analyses with vancomycin stationary phases

Current trends in chiral analysis of pharmaceutical drugs are focused on faster separations and higher separation efficiencies, Core-shell or superficially porous particles （SPP） based chiral stationary phases （CSPs） provide reduced analysis times while maintaining high column efficiencies and sensitivity. In this study, mobile phase conditions suitable for chiral analyses with electrospray ionization LC-MS were systematically investigated using vancomycin as a representative CSP. The performance of a 2.7 μm SPP based vancomycin CSP （SPP-V） 10 cm ×0.21 cm column was compared to that of a corresponding 5 μm fully porous particles based analogue column. The results demonstrated that the SPP-V column provides higher efficiencies, 2-5 time greater sensitivity and shorter analysis time for a set of 22 basic pharma- ceutical drugs. The SPP-V was successfully applied for the analysis of the degradation products of racemic citalopram whose enantiomers could be selectively identified by MS.

Isochronal and isothermal crystallization in Zr_(55)Cu_(30)Ni_5Al_(10) bulk metallic glass

Non-isothermal crystallization transformation kinetics and isothermal crystallization kinetics in super-cooled liquid region（SLR） in Zr55Cu30Ni5Al10 bulk metallic glasses were studied by differential scanning calorimetry（DSC） and X-ray diffraction（XRD）.In isochronal mode,the average values of activation energy in Zr55Cu30Ni5Al10 bulk metallic glass determined by different models（Kissinger method,Flynn-Wall-Ozawa method and Augis-Bennett method） are in good agreement with each other.In addition,the isothermal transformation kinetics in Zr55Cu30Ni5Al10 bulk metallic glasses was described by the Johnson-Mehl-Avrami（JMA） model.For Zr55Cu30Ni5Al10 bulk metallic glass,the Avrami exponent n ranges from 2.2 to 2.9,indicating that crystallization mechanism in the bulk metallic glass was mainly diffusion-controlled;crystal growth is controlled by long range ordering diffusion in three-dimensional growth during isothermal crystallization process.The average value of activation energy in Zr55Cu30Ni5Al10 bulk metallic glass is 469 kJ/mol in isothermal transformation process.

Hydro-mechanical analysis of rainfall-induced fines migration process within unsaturated soils

Seepage-induced fines migration under rainfall infiltration is a main cause leading to shallow failures in loose colluvial slopes. To describe the full process of fines migration within unsaturated soils during rainfall infiltration and the associated hydromechanical behaviors, a seepage-erosion-deformation coupled formulation is proposed in this paper. The governing equations proposed are implemented into a finite element code and used to investigate the influences of skeleton deformation on the rainfall infiltration process through unsaturated soil columns.The numerical results were presented in detail for a better understanding of the rainfall-induced fines migration process within unsaturated soils. Further,the obtained results are integrated into an infinite slope model for slope stability analysis. The results show that, the skeleton deformation will affect the rainfall infiltration rate and hence the timing of slope failures; meanwhile their influences are more evident if the fines deposition process is taken into account.Moreover, the slope stability could be reduced gradually due to the soil strength loss along with loss of fine particles. Therefore, particular attentions should be paid to analyzing the stability of soil slopes susceptible to internal erosion.

Secondary relaxation and dynamic heterogeneity in metallic glasses：A brief review

Understanding mechanical relaxation, such as primary（α） and secondary（β） relaxation, is key to unravel the intertwined relation between the atomic dynamics and non-equilibrium thermodynamics in metallic glasses. At a fundamental level, relaxation, plastic deformation, glass transition, and crystallization of metallic glasses are intimately linked to each other, which can be related to atomic packing, inter-atomic diffusion, and cooperative atom movement. Conceptually, βrelaxation is usually associated with structural heterogeneities intrinsic to metallic glasses. However, the details of such structural heterogeneities, being masked by the meta-stable disordered long-range structure, are yet to be understood. In this paper, we briefly review the recent experimental and simulation results that were attempted to elucidate structural heterogeneities in metallic glasses within the framework of β relaxation. In particular, we will discuss the correlation amongβ relaxation, structural heterogeneity, and mechanical properties of metallic glasses.

Delayed Ionization and Delayed Detachment in Molecules and Clusters

The evolution of a molecular system excited above its ionization threshold depends on a number of parameters that include the nature of the excited states and their couplings to the various continua. The general nature of the processes governing this evolution depends also essentially on the complexity of the molecule, more precisely on its size, density of states, and strength of the couplings among the various internal degrees of freedom. In this paper we address the question of the transition between autoionization that prevails in small molecules, and delayed ionization occurring in larger molecules or clusters. This transition is illustrated by autoionization of Na2 Rydberg states on one hand, delayed ionization in fullerene C60, and delayed detachment in small cluster anions on the other hand. All processes are studied in the case of nanosecond laser excitation, corresponding to a rather slow deposition of the internal energy.

Neuronal networks in mental diseases and neuropathic pain:Beyond brain derived neurotrophic factor and collapsin response mediator proteins

The brain is a complex network system that has the capacity to support emotion, thought, action, learning and memory, and is characterized by constant activity, constant structural remodeling, and constant attempt to compensate for this remodeling. The basic insight that emerges from complex network organization is that substantively different networks can share common key organizational principles. Moreover, the interdependence of network organization and behavior has been successfully demonstrated for several specific tasks. From this viewpoint, increasing experimental/clinical observations suggest that mental disorders are neural network disorders. On one hand, single psychiatric disorders arise from multiple, multifactorial molecular and cellular structural/functional alterations spreading throughout local/global circuits leading to multifaceted and heterogeneous clinical symptoms. On the other hand, various mental diseases may share functional deficits across the same neural circuit as reflected in the overlap of symptoms throughout clinical diagnoses. An integrated framework including experimental measures and clinical observations will be necessary to formulate a coherent and comprehensive understanding of how neural connectivity mediates and constraints the phenotypic expression of psychiatric disorders.

Transdifferentiation of pancreatic α-cells into insulinsecreting cells: From experimental models to underlying mechanisms

Pancreatic insulin-secreting β-cells are essential regulators of glucose metabolism. New strategies are cur-rently being investigated to create insulin-producing β cells to replace deficient β cells, including the differentiation of either stem or progenitor cells, and the newly uncovered transdifferentiation of mature non-β islet cell types. However, in order to correctly drive any cell to adopt a new β-cell fate, a better understanding of the in vivo mechanisms involved in the plasticity and biology of islet cells is urgently required. Here, we review the recent studies reporting the phenomenon of transdifferentiation of α cells into β cells by focusing on the major candidates and contexts revealed to be involved in adult β-cell regeneration through this process. The possible underlying mechanisms of transdifferentiation and the interactions between several key factors involved in the process are also addressed. We propose that it is of importance to further study the molecular and cellular mechanisms underlying α- to β-cell transdifferentiation, in order to make β-cell regeneration from α cells a relevant and realizable strategy for developing cell-replacement therapy.

Designing Discrete Predictor-Based Controllers for Networked Control Systems with Time-varying Delays:Application to A Visual Servo Inverted Pendulum System

A discrete predictor-based control method is developed for a class of linear time-invariant networked control systems with a sensor-to-controller time-varying delay and a controller-to-actuator uncertain constant delay,which can be potentially applied to vision-based control systems.The control scheme is composed of a state prediction and a discrete predictor-based controller.The state prediction is used to compensate for the effect of the sensor-to-controller delay,and the system can be stabilized by the discrete predictor-based controller.Moreover,it is shown that the control scheme is also robust with respect to slight message rejections.Finally,the main theoretical results are illustrated by simulation results and experimental results based on a networked visual servo inverted pendulum system.

Spatial and Temporal Stability of Major and Trace Element Leaching in Urban Stormwater Sediments

Urban sediment generated by stormwater management techniques are highly contaminated with various trace elements. The characterization of trace element speciation and mobility are critical information to improve environmental risk assessment. This study investigates the spatial and temporal variability of major and trace element release from a sedimentary layer in Django Reinhart stormwater infiltration basin (Chassieu, eastern suburbs of Lyon, France). Sampling was conducted for 3 zones and two dates. Chemical characterization was performed (X-Ray diffraction, ICP-AES). The samples were submitted to Acid Neutralization Capacity & Base Neutralization Capacity ANC-BNC tests, according to European standard 14429 (AFNOR, 2015). Solid matrices were mixed with acid or basic solutions and physicochemical parameters and major and trace element release (i.e. Al, Ca, Fe, P, S, Si, Cu, Zn and total carbon) were followed as a function of pH. The results show that the urban sediment has no significant spatial and temporal variability with regards to element release. This observation is all the more surprising that the samples were collected in three contrasting zones regarding stormwater supply and hydric conditions. Element release follows the same trends as a function of pH with a bell-shaped solubilization curve exhibiting with the highest solubility at extreme pH values. However, the samples showed slight differences concerning the release of major elements. Such differences are related to slight differences in total mineral contents (organic matter, carbonates…) and chemical composition of the sediments. The results show that despite the varying environmental conditions, the sediment chemical properties can be considered as very stable and uniform over space, depending mainly on the local geochemical context and watershed characteristics. This study highlights the strength and affluence of the information obtained by ANC-BNC tests on the release of major and traces metal elements by urban sediments and brings relevant information regarding the management of these sediments.

DC/DC变换器稳定性的分析方法

DC/DC变换器属线性混合系统一类.其稳定性分析必须考虑到它们的切换特性.本文介绍一种简单的稳定性分析方法,它可预测被控制的DC/DC变换器在参数变化条件下可能出现的不稳定性及混沌现象.由于它很容易被加入到集成电路的设计流程中,为集成DC/DC变换器设计师提供了一个有效的辅助设计工具.

The role of velocity derivative skewness in understanding non-equilibrium turbulence

The turbulence governed by the Navier-Stokes equation is paramount in many physical processes.However,it has been considered as a challenging problem due to its inherent nonlinearity,non-equilibrium,and complexity.Herein,we review the connections between the velocity derivative skewness Sk and the non-equilibrium properties of turbulence.Sk,a reasonable candidate for describing the non-equilibrium turbulence,which varies during the non-equilibrium procedure.A lot of experimental or numerical evidences have shown that the perturbation of energy spectrum,which associated with the excitation of large scales,results in an obvious variation of Sk,and Sk is a negative value in this rapid energy decay process.The variation of positive Sk is closely related to the perturbation of transfer spectrum,and this corresponds to the backward energy transfer process.In addition,the skewness characterizes the production(or reduction)rate of enstrophy due to vortex stretching(or compression).Using the transport equation of turbulent energy dissipation rate and enstrophy,it is possible to establish a theoretical connection between skewness and the non-equilibrium turbulence.It is expected that this work could trigger the rapid advancement of the future studies of non-equilibrium turbulence,and also the improvement of turbulence models.

Transcranial direct current stimulation in psychiatric disorders

The interest in non-invasive brain stimulation techniques is increasing in recent years. Among these techniques, transcranial direct current stimulation(t DCS) has been the subject of great interest among researchers because of its easiness to use, low cost, benign profile of side effects and encouraging results of research in the field. This interest has generated several studies and randomized clinical trials, particularly in psychiatry. In this review, we provide a summary of the development of the technique and its mechanism of action as well as a review of the methodological aspects of randomized clinical trials in psychiatry, including studies in affective disorders, schizophrenia, obsessive compulsive disorder, child psychiatry and substance use disorder. Finally,we provide an overview of t DCS use in cognitive enhancement as well as a discussion regarding its clinical use and regulatory and ethical issues. Although many promising results regarding t DCS efficacy were described, the total number of studies is still low, highlighting the need of further studies aiming to replicate these findings in larger samples as to provide a definite picture regarding t DCS efficacy in psychiatry.

Screening primary racemic amines for enantioseparation by derivatized polysaccharide and cyclofructan columns

It is a challenge to separate the enantiomers of native chiral amines prone to deleterious silanol interactions. Aset of 39 underivatized chiral primary amines was screened for enantiomeric separation. Seven recentlyintroduced commercial chiral columns were tested. They included six polysaccharide based chiral stationaryphases (CSP) with bonded derivatives, ChiralPak? IA, IB, IC, ID, IE and IF columns and a cyclofructanderivatized CSP, Larihc? CF6-P column. Both the normal phase (NP) mode with heptane/alcohol mobile phasesand the polar organic (PO) mode with acetonitrile/alcohol were evaluated. It was found that the cyclofructanbased CSP demonstrated the highest success rate in separating primary amines in the PO mode with only onechiral amine not resolved. It is shown that, when screening the columns, there is no standard optimal condition;an excellent mobile phase composition for one column may be poorly suited to another one. Althoughbutylamine was a good mobile phase additive for the polysaccharide columns in both PO and NP modes, it wasdetrimental to the enantio-recognition capability of the cyclofructan column. Triethylamine was the appropriatesilanol screening agent for this latter column.

A 13-parameter model for unsaturated soil based on bounding surface plasticity

A few constitutive models for unsaturated soils have already been proposed,however,many classic models such as the Barcelona basic model can simulate neither complex volumetric soil behaviour（without forgetting its supreme merit of being the first consistently and rigorously formulated model） nor post-peak softening,and most advanced models generally comprise a large number of parameters making them more difficult to be applied to practical situations.In this paper,we present a new model for unsaturated soils based on an existing model developed originally for saturated soils.It comprises a minimum number of constitutive parameters.The extension to unsaturated state is achieved by following a general methodology previously developed in our laboratory.The capacities of this simple model are tested.With only 13 parameters,it can reproduce the basic behaviour of unsaturated soils such as rebound or collapse upon wetting,depending on the stress levels.It can also reproduce post-peak softening and transition from contractant to dilatant volumetric behaviour during undrained shear.Overall,the first tentative of validation gives a good correlation between simulations and experimental data,and shows encouraging signs for future developments.

Combined collision-induced dissociation and photo-selected reaction monitoring mass spectrometry modes for simultaneous analysis of coagulation factors and estrogens

Oral estrogens are directly associated with changes in plasma levels of coagulation proteins. Thus, the detection of any variation in protein concentrations due to estrogen contraceptives, by a simultaneous analysis of both coagulation proteins and estrogens, would be a very informative tool. In the present study, the merit of photo-selected reaction monitoring （SRM）, a new analytical tool, was evaluated towards estrogens detection in plasma. Then, SRM and photo-SRM detection modes were combined for the simultaneous analysis of estrogen molecules together with heparin co-factor and factor XIIa, two proteins involved in the coagulation cascade. This study shows that photo-SRM could open new multiplexed analytical routes.

Multi-Level Approach of the Ecotoxicological Impact of a Combined Sewer Overflow on a Peri-Urban Stream

In periurban zones, urban wet weather discharges have been recognized as the most significant vector of pollution in aquatic environments. The discharge of this water without treatment into the aquatic environment could present an ecotoxicological risk for biocenosis. The aim of the INVASION project is to assess the potential ecotoxicological impact of a combined sewer overflow (CSO) on a peri-urban stream. A comparative study between upstream and downstream areas of the CSO allowed observing significant effects of this overflow on the river. We studied three layers of stream: surface water, benthic layer and hyporheic layer. To characterize the potential ecotoxicological risk of water and sediments, we used a battery of 4 bioassays: Daphnia magna, Vibrio fischeri, Brachionus calyciflorus and Heterocypris incongruens. In parallel, we measured the physico-chemical parameters: ammonium (NH4+), chromium (Cr), copper (Cu) and lead (Pb). An ecological risk is greatest for the hyporheic zone in downstream river, particularly for the solid phase. These results corroborated with the physico-chemical data obtained.

Postural spinal balance defined by net intersegmental moments: Results of a biomechanical approach and experimental errors measurement

AIM: To describe initial results and experimental error measurement of a protocol analyzing Human posture through sagittal intersegmental moments. METHODS: Postural analysis has been recently improved by development of three-dimensional radiographic imaging systems. However, in various situations such as global sagittal anterior malalignment interpretation of radiographs may not represent the real alignment of the subject. The aim of this study was to present initial results of a 3D biomechanical protocol. This protocol isobtained in a free standing position and characterizes postural balance by measurement of sagittal intersegmental net moments. After elaboration of a specific marker-set, 4 successive recordings were done on two volunteers by three different operators during three sessions in order to evaluate the experimental error measurement. A supplementary acquisition in a "radiographic" posture was also obtained. Once the data acquired, joint center, length, anatomical frame and the center of mass of each body segment was calculated and a mass affected. Sagittal net intersegmental moments were computed in an ascending manner from ground reaction forces at the ankles, knees, hips and the lumbosacral and thoraco-lumbar spinal junctions. Cervicothoracic net intersegmental moment was calculated in a descending manner.RESULTS: Based on average recordings, clinical interpretation of net intersegmental moments(in N.m) showed a dorsal flexion on the ankles(8.6 N.m), a flexion on the knees(7.5 N.m) and an extension on the hips(8.5 N.m). On the spinal junctions, it was flexion moments: 0.34 N.m on the cervico-thoracic; 6.7 N.m on the thoraco-lumbar and 0.65 N.m on the lumbo-sacral. Evaluation of experimental error measurement showed a small inter-trial error(intrinsic variability), with higher inter-session and inter-therapist errors but without important variation between them. For one volunteer the "radiographic" posture was associated to significant changes compared to the free standing position. CONCLUSION: These initial results confirm the technical feasibility of the protocol. The low intrinsic error and the small differences between inter-session and intertherapist errors seem to traduce postural variability over time, more than a failure of the protocol. Characterization of sagittal intersegmental net moments can have clinical applications such as evaluation of an unfused segment after a spinal arthrodesis.

Tracing Water Flow and Colloidal Particles Transfer in an Unsaturated Soil

In recent years, many studies have been carried out on colloidal particle transfer in the unsaturated zone because they can be a risk to the environment either directly or as a vector of pollutants. A study was conducted on the influence of porous media structure in unsaturated conditions on colloidal particle transport. Three granular materials were set up in columns to replicate a fluvio-glacial soil from the unsaturated zone in the Lyon area (France). It is a sand, a bimodal mixture in equal proportion by weight of sand and gravel, and a fraction of bimodal mixture. Nanoparticles of silica (SiO2-Au-FluoNPs), having a hydrodynamic diameter between 50 and 60 nm, labeled by organic fluorescent molecules were used to simulate the transport of colloidal particles. A nonreactive tracer, bromide ion (Br-) at a concentration of C0,s = 10-2 M was used to determine the hydrodispersive properties of porous media. The tests were carried out first, with a solution of nanoparticles (C0,p = 0.2 g/L) and secondly, with a solution of nanoparticles and bromine. The transfer model based on fractionation of water into two phases, mobile and immobile, MIM, correctly fits the elution curves. The retention of colloidal particles is greater in the two media of bimodal particle size than that in the sand, which clearly demonstrates the role of textural heterogeneity in the retention mechanism. The increase in ionic strength produced by alimenting the columns with colloidal particle suspension in the presence of bromide, increases retention up to 25% in the sand. The total concentration profile of nanoparticles collected at the end of the experiment shows that the colloidal particles are retained primarily at the entrance of the columns. Hydrodispersive calculated parameters indicate that flow is more heterogeneous in bimodal media compared to sand.

Theoretical and Numerical Comparison of Limit Point Bifurcation and Maximum Force Criteria. Application to the Prediction of Diffuse Necking

A large number of criteria has been developed to predict material instabilities, but their choice is limited by the lack of existing comparison of their theoretical basis and application domains. To overcome this limitation, a theoretical and numerical comparison of two major models used to predict diffuse necking is present in this paper. Limit Point Bifurcation criterion is first introduced. An original formulation of the Maximum Force Criterion (MFC), taking into account the effects of damage and isotropic and kinematic hardenings, is then proposed. Strong connections are shown between them by comparing their theoretical basis. Numerical Forming Limit Diagrams at diffuse necking obtained with these criteria for different metallic materials are given. They illustrate the theoretical link and similar predictions are shown for both models.