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Acute kidney injury (AKI) remains a major reason for hospitalization with limited therapeutic options. Although complement activation is implicated in AKI, the role of C5a receptor 1 (C5aR1) in kidney tubular cells is unclear. Herein, aristolochic acid nephropathy (AAN) and folic acid nephropathy (FAN) models were used to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1−/−, myeloid cell–specific, and kidney tubule–specific C5ar1knockout mice. After aristolochic acid and folic acid injection, C5ar1−/−mice had increased AKI severity and a higher degree of tubular injury. Macrophage depletion in C5ar1−/−mice or myeloid cell–specific C5ar1deletion did not affect the outcomes of aristolochic acid–induced AKI. RNA-sequencing data from renal tubular epithelial cells (RTECs) showed that C5ar1deletion was associated with the down-regulation of mitochondrial metabolism and ATP production transcriptional pathways. Metabolic studies confirmed reduced mitochondrial membrane potential at baseline and increased mitochondrial oxidative stress after injury in C5ar1−/−RTECs. Moreover, C5ar1−/−RTECs had enhanced glycolysis, glucose uptake, and lactate production on injury, corroborated by metabolomics analysis of kidneys from AAN mice. Kidney tubule–specific C5ar1knockout mice recapitulated exacerbated AKI observed in C5ar1−/−mice in AAN and FAN. These data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, thereby revealing a novel link between the complement system and tubular cell metabolism.

In this article, we consider the problem of computing from data guaranteed set-valued over-approximations of unknown monotone functions with additive disturbances. We provide a characterization of a simulating map that provably contains all monotone functions that are consistent with the data. This map is also minimal in the sense that any set-valued map containing all consistent monotone functions would also include the map we are proposing. We show that this minimal simulating map is interval-valued and admits a simple construction on a finite partition induced by the data. As the complexity of the partition increases with the amount of data, we also consider the problem of computing minimal interval-valued simulating maps defined on partitions that are fixed a priori. We present an efficient algorithm for their computation. We then use those data-driven over-approximations to build models for partially unknown systems where the unknown part is monotone. The resulting models are used to construct finite-state symbolic abstractions, paving the way for discrete controller synthesis methods to be applied. We extend our approach to handle systems with bounded derivatives and introduce an algorithm to calculate the bounds on those derivatives and on the disturbances from the data. We present several numerical experiments to test the performance of the introduced method and show that the data-driven abstractions are suitable for controller synthesis purposes.

In this paper, we introduce an online safe learning-based Model Predictive Control (MPC) approach. This approach, which we call the ”compatible model approach”, consists of building two models of the system. The first is a piecewise interval-valued over-approximation of the system, and the second is a single-valued piecewise multi-affine estimation of the system’s dynamics. The first model is used to find the set of safe actions at each state, whereas the second is used to choose -out of those safe actions- the input that minimizes a given cost function. For the first model, we use the -assumed known-bounds on the derivative of the dynamics to update the model. The second model should be contained in the first to ensure the feasibility of the MPC scheme everywhere (Hence, the name compatible). Both models can be updated online. We are able to do that because each new transition updates the models locally. We present a test case where we train a mobile robot at low speeds, then navigate it in an environment while avoiding obstacles and collecting new data to learn its dynamics at high speeds.

In Mixed Reality (MR), users' heads are largely (if not completely) occluded by the MR Head-Mounted Display (HMD) they are wearing. As a consequence, one cannot see their facial expressions and other communication cues when interacting locally. In this paper, we investigate how displaying virtual avatars' heads on-top of the (HMD-occluded) heads of participants in a Video See-Through (VST) Mixed Reality local collaborative task could improve their collaboration as well as social presence. We hypothesized that virtual heads would convey more communicative cues (such as eye direction or facial expressions) hidden by the MR HMDs and lead to better collaboration and social presence. To do so, we conducted a between-subject study ($\mathrm{n}=88$) with two independent variables: the type of avatar (CartoonAvatar/RealisticAvatar/NoAvatar) and the level of facial expressions provided (HighExpr/LowExpr). The experiment involved two dyadic communication tasks: (i) the “20-question” game where one participant asks questions to guess a hidden word known by the other participant and (ii) a urban planning problem where participants have to solve a puzzle by collaborating. Each pair of participants performed both tasks using a specific type of avatar and facial animation. Our results indicate that while adding an avatar's head does not necessarily improve social presence, the amount of facial expressions provided through the social interaction does have an impact. Moreover, participants rated their performance higher when observing a realistic avatar but rated the cartoon avatars as less uncanny. Taken together, our results contribute to a better understanding of the role of partial avatars in local MR collaboration and pave the way for further research exploring collaboration in different scenarios, with different avatar types or MR setups.

In virtual reality, the avatar - the user's digital representation - is an important element which can drastically influence the immersive experience. In this paper, we especially focus on the use of “dissimilar” avatars i.e., avatars diverging from the real appearance of the user, whether they preserve an anthropomorphic aspect or not. Previous studies reported that dissimilar avatars can positively impact the user experience, in terms for example of interaction, perception or behaviour. However, given the sparsity and multi-disciplinary character of research related to dissimilar avatars, it tends to lack common understanding and methodology, hampering the establishment of novel knowledge on this topic. In this paper, we propose to address these limitations by discussing: (i) a methodology for dissimilar avatars characterization, (ii) their impacts on the user experience, (iii) their different fields of application, and finally, (iv) future research direction on this topic. Taken together, we believe that this paper can support future research related to dissimilar avatars, and help designers of VR applications to leverage dissimilar avatars appropriately.

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBDNEG; n = 42 anti-RBDLO), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8+%, and SARS-CoV-2–reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBDNEGremained seronegative; 5% KTRs developed BA.5 neutralization (vs 68% HCs, P< .001). Day 30 spike-specific CD8+% was negative in 91% KTRs (vs 20% HCs; P= .07), without correlation to anti-RBD (rs= 0.17). Day 30 SARS-CoV-2–reactive TCR repertoires were detected in 52% KTRs vs 74% HCs (P= .11). Spike-specific CD4+TCR expansion was similar between KTRs and HCs, yet KTR CD8+TCR depth was 7.6-fold lower (P= .001). Global negative response was seen in 7% KTRs, associated with high-dose MMF (P= .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8+responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4+expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263)

In this issue,Yano et al.1present a method to obtain suppressive regulatory T (Treg) cells from human induced pluripotent stem cells (hiPSCs). This approach has the potential to address the low Treg cell yields of current ex vivoTreg cell expansion and induction protocols, an unmet challenge for autologous Treg cell treatments.

Exhaustion of T cells occurs in response to long-term exposure to self and foreign antigens. It limits T cell capacity to proliferate and produce cytokines, leading to an impaired ability to clear chronic infections or eradicate tumors. T-cell exhaustion is associated with a specific transcriptional, epigenetic, and metabolic program and characteristic cell surface markers’ expression. Recent studies have begun to elucidate the role of T-cell exhaustion in transplant. Higher levels of exhausted T cells have been associated with better graft function in kidney transplant recipients. In contrast, reinvigorating exhausted T cells by immune checkpoint blockade therapies, while promoting tumor clearance, increases the risk of acute rejection. Lymphocyte depletion and high alloantigen load have been identified as major drivers of T-cell exhaustion. This could account, at least in part, for the reduced rates of acute rejection in organ transplant recipients induced with thymoglobulin and for the pro-tolerogenic effects of a large organ such as the liver. Among the drugs that are widely used for maintenance immunosuppression, calcineurin inhibitors have a contrasting inhibitory effect on exhaustion of T cells, while the influence of mTOR inhibitors is still unclear. Harnessing or encouraging the natural processes of exhaustion may provide a novel strategy to promote graft survival and transplantation tolerance.

Pepper mild mottle virus (PMMoV), a tobamovirus, has been reported worldwide infecting, especially, pepper plants. In this study, seven new PMMoV isolates were identified in symptomatic pepper plants collected in four departments of Peru. The majority of these isolates induced severe symptoms, including mottle, in susceptible pepper plants. Inoculation on pepper plants carrying four known functional Lresistance alleles (L1, L2, L3, and L4) revealed that PMMoV isolates from Peru belong to the P1,2pathotype. Therefore, pepper species or cultivars with L3and L4alleles displayed hypersensitive response after mechanical inoculation and were still resistant to PMMoV isolates circulating in Peru. Infection by PMMoV was monitored by serology (DAS-ELISA) and RT-PCR with degenerate primers. Virus genes were used to build a phylogenetic tree that showed diversity accumulation among the PMMoV isolates from Peru.

Mammalian red blood cells (RBCs), which primarily contain hemoglobin, exemplify an elaborate maturation process, with the terminal steps of RBC generation involving extensive cellular remodeling. This encompasses alterations of cellular content through distinct stages of erythroblast maturation that result in the expulsion of the nucleus (enucleation) followed by the loss of mitochondria and all other organelles and a transition to anaerobic glycolysis. Whether there is any link between erythroid removal of the nucleus and the function of any other organelle, including mitochondria, remains unknown. Here we demonstrate that mitochondria are key to nuclear clearance. Using live and confocal microscopy and high-throughput single-cell imaging, we show that before nuclear polarization, mitochondria progressively move toward one side of maturing erythroblasts and aggregate near the nucleus as it extrudes from the cell, a prerequisite for enucleation to proceed. Although we found active mitochondrial respiration is required for nuclear expulsion, levels of mitochondrial activity identify distinct functional subpopulations, because terminally maturing erythroblasts with low relative to high mitochondrial membrane potential are at a later stage of maturation, contain greatly condensed nuclei with reduced open chromatin–associated acetylation histone marks, and exhibit higher enucleation rates. Lastly, to our surprise, we found that late-stage erythroblasts sustain mitochondrial metabolism and subsequent enucleation, primarily through pyruvate but independent of in situ glycolysis. These findings demonstrate the critical but unanticipated functions of mitochondria during the erythroblast enucleation process. They are also relevant to the in vitro production of RBCs as well as to disorders of the erythroid lineage.

This article presents a symbolic control approach to the design of distributed safety controllers for a class of continuous-time nonlinear systems. More precisely, we consider systems made of components where each component is equipped with a sampled-data controller with its own sampling period, resulting globally in a distributed multiperiodic sampled-data system. Moreover, controllers receive partial information on the state of the other components. We propose a component-based approach to controller synthesis, which relies on the use of abstractions and continuous-time assume-guarantee contracts. The abstractions describe the dynamics of the system from the point of view of each component based on the information structure, whereas assume-guarantee contracts specify guarantees that a component must satisfy if assumptions on the other components are met. We show that our approach makes it possible to decompose a global safety control problem into local ones that can be solved independently. We then show how symbolic control techniques can be used to synthesize controllers that enforce the local control objectives. Illustrative applications in building automation and vehicle platooning are shown. [ABSTRACT FROM AUTHOR]

We aim at the synthesis of an approximate minimax controlfor a system dynamic given in the form x(t)= f(x(t), u (t), d(t))where xrepresents the state, uthe control (or input) and da disturbance (or perturbation). The disturbance d(t)is prescribed to a compact domain D on which it can take any value (bounded uncertainty).Our method makes use of symbolic computationto enclose the solutions corresponding to all possible disturbance d (-) ϵ D,together with a simple algorithm of random samplingto select the minimum control u⁎(•). We illustrate the interest of this approximate minimax control on an example of a biochemical reactor.

Given a dynamical system Σpwith a parameter ptaking its values in a fixed interval Q, we present a simple criterion of set inclusion which guarantees that the Euler approximate solutions of Σpofor some value po∈ Qconverge to a limit cycle E.Moreover, we characterize a compact set I containing εwhich is invariant for the exact solutions of Σpwhatever the value of p∈ Q.We illustrate the application of our method on the example of a parametric Van der Pol system driven by a periodic input.

In this paper, we present a novel approach for the abstraction of monotone systems with bounded disturbances. The approach is data-driven and uses a given set of samples of the (unknown) dynamics of the system to compute an abstraction defined on partitions of the state and input spaces. The proposed method is efficient as its computational complexity is linear in the number of samples and in the size of the partitions. Moreover, the abstraction is shown to be minimally conservative in the absence of disturbances. We show that the resulting symbolic model is itself a monotone transition system and is related to the original system by an alternating simulation relation. We present some numerical experiments to show the effectiveness of the approach and to show how the choice of the partitions or the number of samples affects the quality of the approximation.

The assembly of the enzyme-activated factor IX (FIXa) with its cofactor, activated factor VIII (FVIIIa) is a crucial event in the coagulation cascade. The absence or dysfunction of either enzyme or cofactor severely compromises hemostasis and causes hemophilia. FIXa is a notoriously inefficient enzyme that needs FVIIIa to drive its hemostatic potential, by a mechanism that has remained largely elusive to date. In this study, we employed hydrogen–deuterium exchange-mass spectrometry (HDX-MS) to investigate how FIXa responds to assembly with FVIIIa in the presence of phospholipids. This revealed a complex pattern of changes that partially overlaps with those changes that occur upon occupation of the substrate-binding site by an active site-directed inhibitor. Among the changes driven by both cofactor and substrate, HDX-MS highlighted several surface loops that have been implicated in allosteric networks in related coagulation enzymes. Inspection of FVIIIa-specific changes indicated that 3 helices are involved in FIXa–FVIIIa assembly. These are part of a basic interface that is also known as exosite II. Mutagenesis of basic residues herein, followed by functional studies, identified this interface as an extended FVIIIa-interactive patch. HDX-MS was also applied to recombinant FIXa variants that are associated with severe hemophilia B. This revealed that single amino acid substitutions can silence the extended network of FVIIIa-driven allosteric changes. We conclude that HDX-MS has the potential to visualize the functional impact of disease-associated mutations on enzyme–cofactor complexes in the hemostatic system.

Tacrolimus (Tac) is an effective anti‐rejection agent in kidney transplantation, but its off‐target effects make withdrawal desirable. Although studies indicate that Tac can be safely withdrawn in a subset of kidney transplant recipients, immune mechanisms that underlie successful vs unsuccessful Tac removal are unknown. We performed microarray analyses of peripheral blood mononuclear cells (PBMC) RNA from subjects enrolled in the Clinical Trials in Organ Transplantation‐09 study in which we randomized stable kidney transplant recipients to Tac withdrawal or maintenance of standard immunosuppression beginning 6 months after transplant. Eight of 14 subjects attempted but failed withdrawal, while six developed stable graft function for ≥2 years on mycophenolate mofetil plus prednisone. Whereas failed withdrawal upregulated immune activation genes, successful Tac withdrawal was associated with a downregulatory and proapoptotic gene program enriched within T cells. Functional analyses suggested stronger donor‐reactive immunity in subjects who failed withdrawal without evidence of regulatory T cell dysfunction. Together, our data from a small, but unique, patient cohort support the conclusion that successful Tac withdrawal is not simply due to absence of donor‐reactive immunity but rather is associated with an active immunological process. Analysis of peripheral blood gene expression profiles in kidney transplant recipients who successfully withdrew from tacrolimus reveals induction of a Treg‐independent, active, pro‐apoptotic program enriched in T cells that is distinct from published B cell signatures observed in operationally tolerant transplant recipients.

Computational mechanistic models constitute powerful tools for summarizing our knowledge in quantitative terms, providing mechanistic understanding, and generating new hypotheses. The present review emphasizes the advantages of reusing publicly available computational models as a way to capitalize on existing knowledge, reduce the number of parameters that need to be adjusted to experimental data, and facilitate hypothesis generation. Finally, it includes a step-by-step example of the reuse and adaptation of an existing model of immune responses to tuberculosis, tumor growth, and blood pathogens, to study donor-specific antibody (DSA) responses. This review aims to illustrate the benefit of leveraging the currently available computational models in immunology to accelerate the study of alloimmune responses, and to encourage modelers to share their models to further advance our understanding of transplant immunology.

ABSTRACTRIO proteins form a conserved family of atypical protein kinases. RIO2 is a serine/threonine protein kinase/ATPase involved in pre-40S ribosomal maturation. Current crystal structures of archaeal and fungal Rio2 proteins report a monomeric form of the protein. Here, we describe three atomic structures of the human RIO2 kinase showing that it forms a homodimer in vitro. Upon self-association, each protomer ATP-binding pocket is partially remodelled and found in an apostate. The homodimerization is mediated by key residues previously shown to be responsible for ATP binding and catalysis. This unusual in vitroprotein kinase dimer reveals an intricate mechanism where identical residues are involved in substrate binding and oligomeric state formation. We speculate that such an oligomeric state might be formed also in vivoand might function in maintaining the protein in an inactive state and could be employed during import.

Continuous antigen stimulation during chronic infection or malignancy can promote functional T cell silencing, a phenomenon called T cell exhaustion. The prevalence and impact of T cell exhaustion following organ transplantation, another immune stimulus with persistently high antigen load, are unknown. Here, we characterized serially collected peripheral blood mononuclear cells from 26 kidney transplant recipients using time-of-flight mass cytometry (CyTOF) to define distinct subsets of circulating exhausted T cells and their relationship to induction therapy and allograft function. We observed an increase in specific subsets of CD4+and CD8+exhausted T cells from pre-transplant to 6-months post-transplant, with greater increases in participants given anti-thymocyte globulin induction than in participants who received no induction or non-depleting induction. The percentages of exhausted T cells at 6 months correlated inversely with adenosine triphosphate (ATP) production (a surrogate of T cell function) and with allograft interstitial fibrosis. Guided by the CyTOF data, we delineated a PD-1+CD57−phenotype for CD4+and CD8+exhausted T cells, and confirmed that these cells have limited capacity for cytokine secretion and ATP production. In an independent cohort of 50 kidney transplant recipients, we confirmed the predicted increase of PD-1+CD57−exhausted T cells after lymphocyte-depleting induction therapy and its direct correlation with better allograft function. Our findings suggest that monitoring T cell exhaustion can be useful for post-transplant risk assessment and support the need to develop and test strategies aimed at augmenting T cell exhaustion following kidney transplantation.

Presents a speech by Michel Fribourg, chairman of Continental Grain Co., delivered to the Second Grain Market Conference in Brussels, Belgium, on May 21, 1986. Global crisis in the agricultural industry; Tension, confrontation and retaliation in agricultural trade; Response of the U.S. government to problems of farm credit; Lessons learned from the efforts of governments in addressing the problem.

Byline: Sylvain Fribourg Author Affiliation: 13652 Cantara St, Panorama City, CA 91402

Costimulatory blockade‐induced murine cardiac allograft survival requires intragraft accumulation of CD11b+Ly6CloLy6G−regulatory myeloid cells (Mregs) that expand regulatory T cells (Tregs) and suppress effector T cells (Teffs). We previously showed that C5a receptor (C5aR1) signaling on T cells activates Teffs and inhibits Tregs, but whether and/or how C5aR1 affects Mregs required for transplant survival is unknown. Although BALB/c hearts survived >60 days in anti‐CD154 (MR1)‐treated or cytotoxic T‐lymphocyte associated protein 4 (CTLA4)‐Ig–treated wild‐type (WT) recipients, they were rejected at ~30 days in MR1‐treated or CTLA4‐Ig–treated recipients selectively deficient in C5aR1 restricted to myeloid cells (C5ar1fl/flxLysM‐Cre). This accelerated rejection was associated with ~2‐fold more donor‐reactive T cells and ~40% less expansion of donor‐reactive Tregs. Analysis of graft‐infiltrating mononuclear cells on posttransplant day 6 revealed fewer Ly6Clomonocytes in C5ar1fl/flxLysM‐Crerecipients. Expression profiling of intragraft Ly6Clomonocytes showed that C5aR1 deficiency downregulated genes related to migration/locomotion without changes in genes associated with suppressive function. Cotransfer of C5ar1fl/fland C5ar1fl/flxLysM‐Cremyeloid cells into MR1‐treated allograft recipients resulted in less accumulation of C5ar1−/−cells within the allografts, and in vitro assays confirmed that Ly6Chimyeloid cells migrate to C5a/C5aR1‐initiated signals. Together, our results newly link myeloid cell–expressed C5aR1 to intragraft accumulation of myeloid cells required for prolongation of heart transplant survival induced by costimulatory blockade. The investigators use conditional knockout mice to demonstrate that monocyte expression of C5a receptor 1 provides important chemoattractant signals that attract regulatory myeloid cells to cardiac allografts and is required for prolonged murine cardiac allograft survival induced by costimulatory blockade. See Riquelme et al's commentary on page 619.

In this paper we propose a monotonicity-based approach for decentralized voltage control of dominantly resistive DC microgrids with ZIP loads. For this purpose, we introduce the notion of set of assignable robust controlled decentralized invariants for the system. Then, upon selection of a desired invariant, an inner decentralized voltage control is designed and a criteria for convergence of the system’s trajectories to an equilibrium point—in presence of constant power loads (CPLs)—is established. Interestingly, a simple realization of the proposed controller corresponds to a piece-wise voltage droop control, the gain of which are determined by the control specifications. A discussion on the selection of appropriate invariants is also carried out and the obtained theoretical results are validated on a 8-terminal benchmark.

ABSTRACTRibosome biogenesis requires a variety of trans-acting factors in order to produce functional ribosomal subunits. In human cells, the complex formed by the proteins hNob1 and hPno1 is crucial to the site 3 cleavage occurring at the 3ʹ-end of 18S pre-rRNA. However, the properties and activity of this complex are still poorly understood. We present here a detailed characterization of hNob1 organization and its interaction with hPno1. We redefine the boundaries of the endonuclease PIN domain present in hNob1 and we further delineate the precise interacting modules required for complex formation in hNob1 and hPno1. Altogether, our data contributes to a better understanding of the complex biology required during the site 3 cleavage step in ribosome biogenesis.

Long‐lived, donor‐reactive memory B cells (Bmems) can produce alloantibodies that mediate transplant injury. Autophagy, an intrinsic mechanism of cell organelle/component recycling, is required for Bmem survival in infectious and model antigen systems, but whether autophagy affects alloreactive Bmem is unknown. We studied mice with an inducible yellow fluorescent protein (YFP) reporter expressed under the activation‐induced cytidine deaminase (AID) promoter active in B cells undergoing germinal center reactions. Up to 12 months after allogeneic sensitization, splenic YFP+B cells were predominantly IgD–IgM–IgG+and expressed CD73, CD80, and PD‐L2, consistent with Bmems. Labeled cells contained significantly more cells with autophagosomes and more autophagosomes per cell than unlabeled, naïve B cells. To test for a functional link, we quantified alloantibody formation in mice with B cells conditionally deficient in the requisite autophagy gene ATG7. These experiments revealed absent B cell ATG7 (1) prevented B cell autophagy, (2) inhibited secondary alloantibody responses without altering primary alloantibody formation, and (3) diminished frequencies of alloreactive Bmems. Pharmacological autophagy inhibition with 3‐methyladenine had similar effects on wild‐type mice. Together with new documentation of increased autophagosomes within human Bmems, our data indicate that targeting autophagy has potential for eliminating donor‐reactive Bmems in transplant recipients. The authors observe increased autophagy in both murine and human memory B cell populations as well as impaired secondary alloantibody responses in sensitized mice treated with an autophagy inhibitor or with conditional B cell deletion of autophagy‐related protein 7.

In this paper, we explain how, under the one-sided Lipschitz (OSL) hypothesis, one can find an error bound for a variant of the Euler-Maruyama approximation method for stochastic switched systems. We then explain how this bound can be used to control stochastic switched switched system in order to stabilize them in a given region. The method is illustrated on several examples of the literature.

This paper considers large discrete-time linear systems obtained from discretized partial differential equations, and controlled by a quantizedlaw, i.e., a piecewise constant time function taking a finite set of values. We show how to generate the control by, first, applying model reductionto the original system, then using a “state-space bisection” method for synthesizing a control at the reduced-order level, and finally computing an upper bound on the deviations between the controlled output trajectories of the reduced-order model and those of the original model. The effectiveness of our approach is illustrated on several examples of the literature.

This article shows that in an in-plane configuration a thin film and a bulk actuators deliver the same amount of mechanical power under the same voltage. This opens the possibility to reach more powerful actuators while keeping the same geometric dimensions by simply stacking these films. It also demonstrates that the effective transverse-plane piezoelectric coefficient is constant with electric field which is a crucial result for this actuator.

Background: Research and development at the edge of micro & nano electronics, nanotechnologies, photonics, materials and biotechnology and their integration into smart miniaturised systems open new opportunities for better quality of life. The area has received substantial public funding and support from the late 90s from the European Union Research Framework Programmes, including the currently running Horizon 2020. We undertook data collection, clustering and analysis of 119 projects (with about 500 M€ EU funding and 890 public and private organisations) covering the area of Micro-Nano-Bio-info technologies and Systems (MNBS) to document the allocation of public money spent on research, development and innovation in this field, to identify synergies, gaps and major trends as well as to verify the alignment with the relevant EU policies and define future challenges and next opportunities for support. Methodology: The projects, funded through several topics of the EC programmes, e.g. Bio-electronics, Biophotonics, Nanomedicine and Healthcare & Well-Being, have been clustered through a semi-automated process based on text mining, using RapidMiner software, with the text describing the projects and their tasks as the input. Text mining-based clustering is grounded in the words contained in the documents provided, and includes basically 2 steps: (i) document pre-processing and (ii) document clustering based on the word frequencies. The hierarchical clustering obtained provide us information related to the proximity of the projects with regard to the meaningful words related to the technologies, processes, applications, etc., which have been kept. This type of grouping provides certainty that projects are grouped with the closest projects in terms of overall content (e.g. objectives, tasks and technologies involved). Results: Classification: Eleven differentiated project categories have been defined, each containing from 6 to 17 projects. These categories can be further re-grouped in broader categories in several ways depending on the purpose, e.g. considering the link to either in-vivo (patient-centred devices) or in-vitro (portable devices and systems and analytical detection platforms) applications, to the level of portability (portable devices vs. platforms), or to the manufacturing importance. Participating (EU and non-EU) organisations include research and academic (37%), private companies (56%), end-users e.g. hospitals or clinical related institutions (4,7%) as well as public authorities and endusers associations in health, food and environment sectors (2,3%). Participation: The participants come from European countries and from Russia, Australia, Japan and the United States. The EU funding is spread all over Europe, though higher concentration is observed in the Western part of Europe. Driving forces: the large majority of projects is driven by two main requirements i.e. avoid the use of specialized laboratory- based (mainly hospital-centred), skilled labour-handled, expensive and time-consuming bio-samples and data analysis; and achieve lower cost, quasi-real-time monitoring or analysis using non-specialized infrastructures, at the Point of Care/Need (out-of-lab). Achievements and Challenges: overall the projects have delivered significant technological progress beyond the state-of-the-art and in some cases integrated prototypes have been validated at the laboratory and in fewer cases tested in real application environments. However, further R&D effort is needed in order to achieve better and compatible interfaces, higher system integration and technology readiness level, better connectivity, efficient manufacturing processes & technologies and validation in real application conditions. Additionally, a critical collaborative effort should be put on effective technology translation of research into new products, speeding up product development, market introduction and cost reduction. This should encompass product design, supply chain setup, user targeting, clinical validation, manufacturing and commercial roll-out. Conclusion: The projects' portfolio analysis allowed sizing the EU funding and clustering of MNBS research and innovation activities, as well as identifying synergies, major trends, gaps and lessons to be learned for future public investment. Supporting further system integration and validation in real life environments as well as the creation of collaborative interdisciplinary platforms and innovation ecosystems will strongly contribute to new business and markets. It will accelerate the digitization of the European industry in key sectors like healthcare, food and security and support innovation through the full supply chains, thus will positively impact the EU's single market fit for the digital age.

We report on the realization of relaxor ferroelectric thin films by rf magnetron sputtering deposition. We investigated fabrication of films in the solid solution of PMN (Pb(Mg1/3Nb2/3)O3) with PT (PbTiO3). This material is the most studied among the relaxor ferroelectric family for applications in the field of microelectronics and microsystems. We chose the composition with 30% of PT, close to the morphotropic phase boundary between relaxor and normal ferroelectric behavior which exhibits good piezoelectric properties suited to actuators. We have grown the films in a cold deposition process. The substrates used were Si/SiO2coated by Ti/Pt electrodes. This allowed to synthesize pyrochlore-free PMNT ceramic thin films at temperatures between 450 and 675°C in a postdeposition conventional annealing. We performed dielectric and ferroelectric characterizations of the films with Pt upper electrodes. Dielectric constant was measured as a function of temperature (up to 155°C) and frequency (1 kHz ~ 1 MHz). We obtained relative dielectric constant of the order of 1500. Relaxor behavior and ferroelectric properties are evidenced and are shown to be enhanced by annealing temperature.

Molineus torulosus(Molin, 1861) parasite of Cebusspp. from South America is redescribed in Cebus apellaand C. olivecaeus(new host) from French Guyana with emphasis on the synlophe. During the maturation process, the larvae dwelt in the cysts carved alongside the external part of the small intestine. The turn-out of the mature worms and the laid eggs depended on the tissular organisation of cyst walls as the inflammatory process waned and fibrosis progressed to seal the cystic lumen. Adult worms entwine themselves in the cysts, live there permanently as their presence has never been evidenced in the intestinal lumen. They copulated, laid eggs, degenerated and died once entrapped by the fibrotic process. Laid eggs released in the intestinal lumen through a narrow channel ensured the continuation of the developmental cycle. However, erratic migration was possible via the vascular channels surrounding the cysts.

High frequencies of donor-reactive memory T cells in the periphery of transplant candidates prior to transplantation are linked to the development of post-transplant acute rejection episodes and to reduced allograft function. Rabbit anti-thymocyte globulin (rATG) effectively depletes naïve CD4+and CD8+T cells for > 6 months post-transplant, but rATG’s effects on human donor-reactive T cells have not been carefully determined. To address this, we performed T cell receptor beta chain sequencing (TCRseq) on PBMC aliquots collected pre-transplant and serially post-transplant in seven kidney transplant recipients who received rATG as induction therapy. We tracked the evolution of the donor-reactive CD4+and CD8+T cell repertoires, identified stimulated pre-transplant, CTV-(surface dye)-labeled, PBMC from each patient with donor cells or third-party cells. Our analyses showed that while rATG depleted CD4+T cells in all tested subjects, a subset of donor-reactive CD8+T cells that were present at high frequencies pre-transplant, consistent with expanded memory cells, resisted rATG depletion, underwent post-transplant expansion and were functional. Together, our data support the conclusion that a subset of human memory CD8+T cells specifically reactive to donor antigens expand in vivo despite induction therapy with rATG and thus have the potential to mediate allograft damage.

In this paper, we introduce a novel approach to safe learning-based Model Predictive Control (MPC) for nonlinear systems. This approach, which we call the “compatible model approach”, relies on computing two models of the given unknown system using data generated from the system. The first model is a set-valued over-approximation guaranteed to contain the system’s dynamics. This model is used to find a set of provably safe controller actions at every state. The second model is a single-valued estimation of the system’s dynamics used to find a controller that minimises a cost function. If the two models are compatible, in the sense that the estimation is included in the over-approximation, we show that we can use the set of safe controller actions to constrain the minimisation problem and guarantee the feasibility and safety of the learning-based MPC controller at all times. We present a method to build an over-approximation for nonlinear systems with bounded derivatives on a partition of the states and inputs spaces. Then, we use piecewise multi-affine functions (defined on the same partition) to calculate a system’s dynamics estimation that is compatible with the previous over-approximation. Finally, we show the effectiveness of the approach by considering a path-planning problem with obstacle avoidance.

In his "Guns of the West" article on Colt's big Model 1898 (December 2006), Lee A. Silva writes, "Sam Colt did not invent the revolver." I would be interested to […]

Your item on 'The Bovine Menace' (Primary Sources, March Atlantic) claims that 'animal flatulence' is responsible for greenhouse-gas emissions. In fact, there is essentially no methane produced in such a […]

Les systèmes de gestion des eaux urbaines ont largement évolué pour s’adapter au développement de nos villes et à des pressions croissantes liées à l’augmentation de l’urbanisation et à la densification des activités humaines [Patouillard, 2014]. Les dispositifs mis en oeuvre se sont diversifiés à travers l’Europe et la tendance actuelle est le « verdissement » de ces techniques, notamment sous l’impulsion de la Commission européenne qui légifère ou incite en ce sens, dans le contexte de changement climatique, afin de sécuriser la gestion des ressources en eau de l’Europe. De nombreux termes tels que ingénierie écologique, techniques alternatives, mesures naturelles de rétention d’eau, etc., émergent pour qualifier des techniques novatrices ou non, mais qui présentent toutes l’avantage de combiner de nombreux bénéfices pour l’environnement. Ces techniques présentent un ratio coût/efficacité potentiellement favorable vis-à-vis des infrastructures grises classiques, qui sont de plus souvent limitées à un seul objectif. Dans ce contexte, le projet européen « NWRM » (achevé en avril 2015), dont une partie des résultats est présentée dans cet article, a rassemblé une grande partie de la connaissance sur les NWRM via une plateforme Internet accessible à tous, et a participé à fédérer une communauté de pratiques autour de ces mesures.Cette communication contient une description des douze mesures labellisées « NWRM » (natural water retention measures) adaptées au milieu urbain et la présentation de deux études de cas : 1°) la transformation d’une route résidentielle par l’installation de jardins pluviaux (Nottingham, Royaume-Uni), et 2°) la mise en oeuvre d’une combinaison ingénieuse de plusieurs NWRM à plus large échelle pour la reconversion d’une friche industrielle (Fornebu, Norvège). Sont présentés également certains des outils qui ont été développés dans le cadre de ce projet européen pour soutenir les maîtres d’ouvrage et les décideurs politiques dans la sélection, la conception et la mise en oeuvre de NWRM.

Porous polymeric aromatic frameworks (PAFs) have high porosity and surface area, as well as high physicochemical stability; such characteristics are important in the design of heterogeneous catalysts with high catalytic efficiency and recyclability. This paper presents the synthesis, characterization, post-functionalization and catalytic performance of the resulting modified PAFs based on tetraphenyladamantane (PAFAd), tetraphenylmethane (PAFC) and 9,9′-spirobisfluorene (PAFspf) nodes. The PAFs were obtained by the Suzuki–Miyaura cross-coupling under microwave heating, and were sequentially reacted with 1-(chloromethoxy)octane and 1-mesityl-1H-imidazole or 2-(1H-imidazol-1-yl)pyridine to yield the corresponding imidazolium chloride derivative (PAF-Im) which readily formed stable N-heterocyclic carbene (NHC) iridium and ruthenium complexes (PAF-(NHC)Ir, PAF-(NHC)Ru). The materials were characterized by solid-state NMR spectroscopy, FTIR spectroscopy, and textural analysis. The PAF-(NHC)Mmaterials display excellent catalytic performance in the N-alkylation of amines with alcohols and transfer hydrogenation of ketones over multiple catalytic cycles.

In the gradient descent method, one often focus on the convergence of the sequence generated by the algorithm, but less often on the deviation of these points from the solutions of the original continuous-time differential equation (gradient flow). This also happens when discretizing other ordinary differential equations. In the case of a discretization by explicit Euler’s method with a constant step h, we provide here sufficient conditions, in terms of strong monotonicity and co-coercivity, for the deviation between discrete and continuous solutions to tend asymptotically towards zero. This analysis could shed new light on some applications of the gradient descent algorithm.

The winged helix (WH) domain is found in core components of transcription systems in eukaryotes and prokaryotes. It represents a sub-class of the helix-turn-helix motif. The WH domain participates in establishing protein-DNA and protein-protein-interactions. Here, we discuss possible explanations for the enrichment of this motif in transcription systems.

The Cleavage stimulation Factor (CstF) complex is composed of three subunits and is essential for pre-mRNA 3'-end processing. CstF recognizes U and G/U-rich cis-acting RNA sequence elements and helps stabilize the Cleavage and Polyadenylation Specificity Factor (CPSF) at the polyadenylation site as required for productive RNA cleavage. Here, we describe the crystal structure of the N-terminal domain of Drosophila CstF-50 subunit. It forms a compact homodimer that exposes two geometrically opposite, identical, and conserved surfaces that may serve as binding platform. Together with previous data on the structure of CstF-77, homodimerization of CstF-50 N-terminal domain supports the model in which the functional state of CstF is a heterohexamer.

L’anémie de Diamond-Blackfan (ADB) est une érythroblastopénie (absence ou déficit sévère des érythroblastes dans la moelle osseuse) congénitale associée à des mutations hétérozygotes dans des gènes codant des protéines ribosomiques. Des études récentes indiquent que ces mutations ont pour effet premier d’affecter la synthèse des ribosomes. L’explication du lien physiopathologique inattendu entre ce processus ubiquitaire et une maladie affectant particulièrement l’érythropoïèse pourrait en partie se trouver dans la notion émergente de « stress ribosomique », une voie d’arrêt du cycle cellulaire activée en réponse à un défaut de production des ribosomes. L’ADB est devenue un paradigme pour étudier le nombre croissant des maladies liées à la mutation de gènes codant des protéines entrant en jeu dans la biogenèse des ribosomes.