ALBERT

Description: Introduction Systemic Lupus Erythematosus (SLE) is associated with thrombocytopenia in approximately 20 % of cases. Management of such cases has been similar to that of Immune ThrombocytoPenia (ITP) as an immune-mediated mechanism is inferred in the pathogenesis of SLE-associated thrombocytopenia. First line treatment is similar to primary ITP (corticosteroids, intravenous immunoglobulin), with the use of hydroxychloroquin in addition. Immunosuppressive agents, rituximab or splenectomy can be used as second line treatment. However, a significant number of patients will not respond to these treatments and will relapse afterward. More recently, Romiplostim and Eltrombopag, 2 agonists of thrombopoietin receptor (TPO-RA) have been approved for ITP as second line therapy resulting in sustained increment in platelet count in about 70-80 % of cases with reduction in bleeding. However, the experience with this class of agents in SLE is only anecdotal. Their effectiveness and side effects in SLE related ITP is unknown. Patients and Method This was a multicenter retrospective cohort study of patients with SLE related ITP diagnosed from 1998 to 2015 and treated with TPO-RA. All participating centers (n=13) were secondary or tertiary care hospitals belonging to the French national network for adult ITP. Clinical data were retrospectively collected from medical charts for each patient and completed by telephone interviews with patients and physicians by using a standardized questionnaire. ITP was defined according to the international working group definitions. SLE was defined according to the international guidelines (American College of Rheumatology for systemic lupus erythematosus, revised Sapporo criteria for antiphospholipid syndrome). Response (R) and complete response (CR) were defined according to standardized international criteria: platelet count 〉 30 × 109/L with at least a doubling of the baseline value or 〉100 × 109/L.2 Non-response (NR) was defined as the absence of platelet count increase 〉30 × 109/L with at least a doubling of the baseline count or the need for rescue therapy (IVIg and/or corticosteroids). Patient's characteristics (table 1&2) PS: PitiŽ Salptrire, F: female, M: male, HCQ: hydroxychloroquin, MMF: Mycophenolate mofetil, CTC: corticosteroid, RTX : rituximab, CYC: cyclophosphamide, IVIG : intravenous immunoglobulin, AZA: azathioprine, spm: splenectomy, Toci: tocilizumab, Aba: abatacept, Csa: ciclosporine, TPO-RA : thrombopoietin-receptor agonist, Elt : eltrombopag, Romipl : romiplostim, NS :non specified, CR: complete remission, R :responder, NR :non responder APLS: antiphospholipid syndrome, APL : antiphospholipid (presence of antibody without clinical symptoms) Results and Discussion A total of 16 patients (12 F/ 4M) received TPO-RA (Romiplostim 36%, eltrombopag 28 %, both 36%). Patients had received a median of 5.5 treatment lines for ITP. All but one patient responded at least to one of TPO-RA (93%). No SLE flare has been observed with these treatments. Unexpectedly, 3 patients (18,5%) developed thrombotic events as a side effect. Two arterial thrombosis occurred in patients receiving eltrombopag (both of them with a previous history of APL or APLS), and two venous thrombosis in the same patient (without antiphospholipid) treated with romiplostim. The same strategy was used in the 3 patients: TPO-RA was stopped but rechallenged promptly to increase platelet level, given that they were receiving anticoagulant or anti-aggregant therapy. No reoccurrence has been observed. The other side effects were similar to that observed with primary ITP. This study has some limitations due to its retrospective design, including some potential selection bias but the rapid and sustained response observed raises the possibility that in certain refractory cases of thrombocytopenia associated with SLE, TPO-RA might be a second line therapy to be considered in this patient population. Given the high rate of thrombotic events, we suggest that TPO-RA should be used with caution in patient with APL. Prospective systematic studies would help define the role of this class of agents in SLE and other rheumatic disease that progress with immune mediated thrombocytopenia. Table 1 Table 1. Table 2 Table 2. Disclosures Terriou: amgen: Consultancy; Novartis: Consultancy. Bussel:Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; BiologicTx: Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; Sysmex: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding.

Description: Agricultural landscape homogenization has detrimental effects on biodiversity and key ecosystem services. Increasing agricultural landscape heterogeneity by increasing seminatural cover can help to mitigate biodiversity loss. However, the amount of seminatural cover is generally low and difficult to increase in many intensively managed agricultural landscapes. We hypothesized that increasing the heterogeneity of the crop mosaic itself (hereafter “crop heterogeneity”) can also have positive effects on biodiversity. In 8 contrasting regions of Europe and North America, we selected 435 landscapes along independent gradients of crop diversity and mean field size. Within each landscape, we selected 3 sampling sites in 1, 2, or 3 crop types. We sampled 7 taxa (plants, bees, butterflies, hoverflies, carabids, spiders, and birds) and calculated a synthetic index of multitrophic diversity at the landscape level. Increasing crop heterogeneity was more beneficial for multitrophic diversity than increasing seminatural cover. For instance, the effect of decreasing mean field size from 5 to 2.8 ha was as strong as the effect of increasing seminatural cover from 0.5 to 11%. Decreasing mean field size benefited multitrophic diversity even in the absence of seminatural vegetation between fields. Increasing the number of crop types sampled had a positive effect on landscape-level multitrophic diversity. However, the effect of increasing crop diversity in the landscape surrounding fields sampled depended on the amount of seminatural cover. Our study provides large-scale, multitrophic, cross-regional evidence that increasing crop heterogeneity can be an effective way to increase biodiversity in agricultural landscapes without taking land out of agricultural production.

Description: The α7 nicotinic acetylcholine receptor (nAChR) belongs to the family of pentameric ligand-gated ion channels and is involved in fast synaptic signaling. In this study, we take advantage of a recently identified chimera of the extracellular domain of the native α7 nicotinic acetylcholine receptor and acetylcholine binding protein, termed α7-AChBP. This chimeric receptor was used to conduct an innovative fragment-library screening in combination with X-ray crystallography to identify allosteric binding sites. One allosteric site is surface-exposed and is located near the N-terminal α-helix of the extracellular domain. Ligand binding at this site causes a conformational change of the α-helix as the fragment wedges between the α-helix and a loop homologous to the main immunogenic region of the muscle α1 subunit. A second site is located in the vestibule of the receptor, in a preexisting intrasubunit pocket opposite the agonist binding site and corresponds to a previously identified site involved in positive allosteric modulation of the bacterial homolog ELIC. A third site is located at a pocket right below the agonist binding site. Using electrophysiological recordings on the human α7 nAChR we demonstrate that the identified fragments, which bind at these sites, can modulate receptor activation. This work presents a structural framework for different allosteric binding sites in the α7 nAChR and paves the way for future development of novel allosteric modulators with therapeutic potential.

Description: Here we asked the question whether fluorescence labelled small molecule agonists of the α 7 nicotinic acetylcholine receptor (nAChR) might be identified to enhance receptor studies. Enantiomerically pure 3-amino-quinuclidines appended with fluorophores at the 3-amino group were synthesized and tested by electrophysiology on human α 7 nAChR in Xenopus oocytes, uncovering ( R )-4 and ( R )-9 as the first examples of fluorescent α 7 nAChR agonists. These molecules elegantly incorporate the fluorescent reporter group as part of the pharmacophore itself and provide a new class of tool compounds for the study of these ligand gated ion channels. This article is protected by copyright. All rights reserved.

Description: The α7 nicotinic acetylcholine receptor (nAChR) belongs to the family of pentameric ligand-gated ion channels and is involved in fast synaptic signaling. In this study, we take advantage of a recently identified chimera of the extracellular domain of the native α7 nicotinic acetylcholine receptor and acetylcholine binding protein, termed α7-AChBP....

Description: In this paper, a stride detector algorithm combined with a technique inspired by zero velocity update (ZUPT) is proposed to reconstruct the trajectory of a pedestrian from an ankle-mounted inertial device. This innovative approach is based on sensor alignment and machine learning. It is able to detect 100% of both normal walking strides and more than 97% of atypical strides such as small steps, side steps, and backward walking that existing methods can hardly detect. This approach is also more robust in critical situations, when for example the wearer is sitting and moving the ankle or when the wearer is bicycling (less than two false detected strides per hour on average). As a consequence, the algorithm proposed for trajectory reconstruction achieves much better performances than existing methods for daily life contexts, in particular in narrow areas such as in a house. The computed stride trajectory contains essential information for recognizing the activity (atypical stride, walking, running, and stairs). For this task, we adopt a machine learning approach based on descriptors of these trajectories, which is shown to be robust to a large of variety of gaits. We tested our algorithm on recordings of healthy adults and children, achieving more than 99% success. The algorithm also achieved more than 97% success in challenging situations recorded by children suffering from movement disorders. Compared to most algorithms in the literature, this original method does not use a fixed-size sliding window but infers this last in an adaptive way.

Description: Motivation : A vast literature from the past decade is devoted to relating gene profiles and subject survival or time to cancer recurrence. Biomarker discovery from high-dimensional data, such as transcriptomic or single nucleotide polymorphism profiles, is a major challenge in the search for more precise diagnoses. The proportional hazard regression model suggested by Cox (1972), to study the relationship between the time to event and a set of covariates in the presence of censoring is the most commonly used model for the analysis of survival data. However, like multivariate regression, it supposes that more observations than variables, complete data, and not strongly correlated variables are available. In practice, when dealing with high-dimensional data, these constraints are crippling. Collinearity gives rise to issues of over-fitting and model misidentification. Variable selection can improve the estimation accuracy by effectively identifying the subset of relevant predictors and enhance the model interpretability with parsimonious representation. To deal with both collinearity and variable selection issues, many methods based on least absolute shrinkage and selection operator penalized Cox proportional hazards have been proposed since the reference paper of Tibshirani. Regularization could also be performed using dimension reduction as is the case with partial least squares (PLS) regression. We propose two original algorithms named sPLSDR and its non-linear kernel counterpart DKsPLSDR, by using sparse PLS regression (sPLS) based on deviance residuals. We compared their predicting performance with state-of-the-art algorithms on both simulated and real reference benchmark datasets. Results : sPLSDR and DKsPLSDR compare favorably with other methods in their computational time, prediction and selectivity, as indicated by results based on benchmark datasets. Moreover, in the framework of PLS regression, they feature other useful tools, including biplots representation, or the ability to deal with missing data. Therefore, we view them as a useful addition to the toolbox of estimation and prediction methods for the widely used Cox’s model in the high-dimensional and low-sample size settings. Availability and implementation : The R-package plsRcox is available on the CRAN and is maintained by Frédéric Bertrand. http://cran.r-project.org/web/packages/plsRcox/index.html . Contact : pbastien@rd.loreal.com or fbertran@math.unistra.fr . Supplementary information : Supplementary data are available at Bioinformatics online.

Description: In fluctuating environments, matching breeding timing to periods of high resource availability is crucial for the fitness of many vertebrate species, and may have major consequences on population health. Yet, our understanding of the proximate environmental cues driving seasonal breeding is limited. This is particularly the case in marine ecosystems, where key environmental factors and prey abundance and availability are seldom quantified. The Northern Humboldt Current System (NHCS) is a highly productive, low-latitude ecosystem of moderate seasonality. In this ecosystem, three tropical seabird species (the Guanay Cormorant Phalacrocorax bougainvillii , the Peruvian Booby Sula variegata , and the Peruvian Pelican Pelecanus thagus ) live in sympatry and prey almost exclusively on anchovy, Engraulis ringens . From January 2003 to December 2012, we monitored 31 breeding sites along the Peruvian coast to investigate the breeding cycle of these species. We tested for relationships between breeding timing, oceanographic conditions, and prey availability using occupancy models. We found that all three seabird species exhibited seasonal breeding patterns, with marked interspecific differences. Whereas breeding mainly started during the austral winter/early spring and ended in summer/early fall, this pattern was stronger in boobies and pelicans than in cormorants. Breeding onset mainly occurred when upwelling was intense but ecosystem productivity was below its annual maxima, and when anchovy were less available and in poor physiological condition. Conversely, the abundance and availability of anchovy improved during chick rearing and peaked around the time of fledging. These results suggest that breeding timing is adjusted so that fledging may occur under optimal environmental conditions, rather than being constrained by nutritional requirements during egg laying. Adjusting breeding time so that fledglings meet optimal conditions at independence is unique compared with other upwelling ecosystems and could be explained by the relatively high abundances of anchovy occurring throughout the year in the NHCS.

Description: An early assessment of biological invasions is important for initiating conservation strategies. Instrumental progress in high spatial resolution (HSR) multispectral satellite sensors greatly facilitates ecosystems’ monitoring capability at an increasingly smaller scale. However, species detection is still challenging in environments characterized by a high variability of vegetation mixing along with other elements, such as water, sediment, and biofilm. In this study, we explore the potential of Pléiades HSR multispectral images to detect and monitor changes in the salt marshes of the Bay of Arcachon (SW France), after the invasion of Spartina anglica. Due to the small size of Spartina patches, the spatial and temporal monitoring of Spartina species focuses on the analysis of five multispectral images at a spatial resolution of 2 m, acquired at the study site between 2013 and 2017. To distinguish between the different types of vegetation, various techniques for land use classification were evaluated. A description and interpretation of the results are based on a set of ground truth data, including field reflectance, a drone flight, historical aerial photographs, GNSS and photographic surveys. A preliminary qualitative analysis of NDVI maps showed that a multi-temporal approach, taking into account a delayed development of species, could be successfully used to discriminate Spartina species (sp.). Then, supervised and unsupervised classifications, used for the identification of Spartina sp., were evaluated. The performance of the species identification was highly dependent on the degree of environmental noise present in the image, which is season-dependent. The accurate identification of the native Spartina was higher than 75%, a result strongly affected by intra-patch variability and, specifically, by the presence of areas with a low vegetation density. Further, for the invasive Spartina anglica, when using a supervised classifier, rather than an unsupervised one, the accuracy of the classification increases from 10% to 90%. However, both algorithms highly overestimate the areas assigned to this species. Finally, the results highlight that the identification of the invasive species is highly dependent both on the seasonal presence of itinerant biological features and the size of vegetation patches. Further, we believe that the results could be strongly improved by a coupled approach, which combines spectral and spatial information, i.e., pattern-recognition techniques.