Handling congestion in crowd motion modeling

We address here the issue of congestion in the modeling of crowd motion, in the non-smooth framework: contacts between people are not anticipated and avoided, they actually occur, and they are explicitly taken into account in the model. We limit our approach to very basic principles in terms of behavior, to focus on the particular problems raised by the non-smooth character of the models. We consider that individuals tend to move according to a desired, or spontanous, velocity. We account for congestion by assuming that the evolution realizes at each time an instantaneous balance between individual tendencies and global constraints (overlapping is forbidden): the actual velocity is defined as the closest to the desired velocity among all admissible ones, in a least square sense. We develop those principles in the microscopic and macroscopic settings, and we present how the framework of Wasserstein distance between measures allows to recover the sweeping process nature of the problem on the macroscopic level, which makes it possible to obtain existence results in spite of the non-smooth character of the evolution process. Micro and macro approaches are compared, and we investigate the similarities together with deep differences of those two levels of description

The Role of miRNAs from the 14q32 Region in Acquired Resistance to Lapatinib

PhD thesisHER2 is over-expressed in 20-25 % of breast cancers. Due to the increase in proliferation and survival signalling resulting from HER2 over-expression, this sub-type is associated with more aggressive tumour progression and poor prognosis. HER2 targeted-therapy has significantly improved patient prognosis, however, despite all progress only a subgroup derives optimal benefit, whereas others have refractory disease or develop resistance. It is therefore necessary to identify new targets to improve patient outcome. A group of non-coding RNAs, miRNAs, are often aberrantly expressed in tumours and miRNA expression profiles have been seen to evolve over the course of treatment implicating them in therapeutic resistance. Using the lapatinib sensitive, BT-474, and resistant, BT-474/L, HER2 expressing cells, 44 miRNAs were found to be upregulated. The region with the highest number of differentially expressed miRNAs is the 14q32 region. RTqPCR confirmed upregulation of 14q32 miRNAs in the BT-474/L compared to BT-474 as well as 2 other pairs (HCC1954, HCC1954/L, and SKBR-3, SKBR- 3/L) linking increased miRNA expression with acquired resistance to lapatinib. As the 14q32 region is regulated by DNA imprinting, we explored epigenetic changes between the sensitive and resistant lines. Global methylation reversal cased upregulation of all three miRNAs in the sensitive cells. This suggests loss of methylation is a key in controlling 14q32 miRNA expression. Since miRNAs are not suitable therapeutic targets, differential gene expression analysis combined with in silico analysis was used to identify targets of the miRNAs. Silencing of five target genes seemed to decrease sensitivity of the cells to HER2-targeted treatment. Analysis of the NeoALTTO clinical trial data suggests high expression of four of these genes, SOCS2, BASP1, NEDD4L, and SH3BGRL could be linked to better prognosis. These results suggest upregulation of 14q32 miRNAs caused by loss of epigenetic regulation leads to decreased expression of SOCS2, BASP1, NEDD4L, and SH3BGRL. This loss could contribute to HER2-targeted therapy resistance. Therefore expression levels of 14q32 miRNAs could be used as a prognostic biomarker to identify patients likely to relapse.Breast Cancer No

Progress in Atomic Fountains at LNE-SYRTE

We give an overview of the work done with the Laboratoire National de M\'etrologie et d'Essais-Syst\`emes de R\'ef\'erence Temps-Espace (LNE-SYRTE) fountain ensemble during the last five years. After a description of the clock ensemble, comprising three fountains, FO1, FO2, and FOM, and the newest developments, we review recent studies of several systematic frequency shifts. This includes the distributed cavity phase shift, which we evaluate for the FO1 and FOM fountains, applying the techniques of our recent work on FO2. We also report calculations of the microwave lensing frequency shift for the three fountains, review the status of the blackbody radiation shift, and summarize recent experimental work to control microwave leakage and spurious phase perturbations. We give current accuracy budgets. We also describe several applications in time and frequency metrology: fountain comparisons, calibrations of the international atomic time, secondary representation of the SI second based on the 87Rb hyperfine frequency, absolute measurements of optical frequencies, tests of the T2L2 satellite laser link, and review fundamental physics applications of the LNE-SYRTE fountain ensemble. Finally, we give a summary of the tests of the PHARAO cold atom space clock performed using the FOM transportable fountain.Comment: 19 pages, 12 figures, 5 tables, 126 reference

Atomic fountains and optical clocks at SYRTE: status and perspectives

In this article, we report on the work done with the LNE-SYRTE atomic clock ensemble during the last 10 years. We cover progress made in atomic fountains and in their application to timekeeping. We also cover the development of optical lattice clocks based on strontium and on mercury. We report on tests of fundamental physical laws made with these highly accurate atomic clocks. We also report on work relevant to a future possible redefinition of the SI second

Metabolomics and Lipidomics Profiling of a Combined Mitochondrial Plus Endoplasmic Reticulum Fraction of Human Fibroblasts: A Robust Tool for Clinical Studies

Mitochondria and endoplasmic reticulum (ER) are physically and functionally connected. This close interaction, via mitochondria-associated membranes, is increasingly explored and supports the importance of studying these two organelles as a whole. Metabolomics and lipidomics are powerful approaches for the exploration of metabolic pathways that may be useful to provide deeper information on these organelles\u27 functions, dysfunctions, and interactions. We developed a quick and simple experimental procedure for the purification of a mitochondria-ER fraction from human fibroblasts. We applied combined metabolomics and lipidomics analyses by mass spectrometry with excellent reproducibility. Seventy-two metabolites and 418 complex lipids were detected with a mean coefficient of variation around 12%, among which many were specific to the mitochondrial metabolism. Thus this strategy based on robust mitochondria-ER extraction and "omics" combination will be useful for investigating the pathophysiology of complex diseases

Nouméa: a new multi-mission calibration and validation site for past and future altimetry missions?

Today, monitoring the evolution of sea level in coastal areas is of importance, since almost 11 % of the world's population lives in low-lying areas. Reducing uncertainties in sea level estimates requires a better understanding of both altimetry measurements and local sea level dynamics. In New Caledonia, the Nouméa lagoon is an example of this challenge, as altimetry, coastal tide gauge, and vertical land motions from global navigation satellite systems (GNSSs) do not provide consistent information. The GEOCEAN-NC 2019 field campaign addresses this issue with deployments of in situ instruments in the lagoon (GNSS buoy, pressure gauge, etc.), with a particular focus on the crossover of one Jason-series track and two Sentinel-3A missions tracks. In this study, we propose a method to virtually transfer the Nouméa tide gauge at the altimetry crossover point, using in situ data from the field campaign. Following the philosophy of calibration and validation (Cal/Val) studies, we derive absolute altimeter bias time series over the entire Jason and Sentinel-3A periods. Overall, our estimated altimeter mean biases are slightly larger by 1–2 cm compared to Corsica and Bass Strait results, with inter-mission biases in line with those of Bass Strait site. Uncertainties still remain regarding the determination of our vertical datum, only constrained by the three days of the GNSS buoy deployment. With our method, we are able to re-analyse about 20 years of altimetry observations and derive a linear trend of −0.2 ± 0.1 mm yr−1 over the bias time series. Compared to previous studies, we do not find any significant uplift in the area, which is more consistent with the observations of inland permanent GNSS stations. These results support the idea of developing Cal/Val activities in the lagoon, which is already the subject of several experiments for the scientific calibration phase of the SWOT wide-swath altimetry mission.</p

Lipidomics Reveals Triacylglycerol Accumulation Due to Impaired Fatty Acid Flux in Opa1-Disrupted Fibroblasts

OPA1 is a dynamin GTPase implicated in mitochondrial membrane fusion. Despite its involvement in lipid remodeling, the function of OPA1 has never been analyzed by whole-cell lipidomics. We used a nontargeted, reversed-phase lipidomics approach, validated for cell cultures, to investigate OPA1-inactivated mouse embryonic fibroblasts ( Opa1 MEFs). This led to the identification of a wide range of 14 different lipid subclasses comprising 212 accurately detected lipids. Multivariate and univariate statistical analyses were then carried out to assess the differences between the Opa1 and Opa1 genotypes. Of the 212 lipids identified, 69 were found to discriminate between Opa1 MEFs and Opa1 MEFs. Among these lipids, 34 were triglycerides, all of which were at higher levels in Opa1 MEFs with fold changes ranging from 3.60 to 17.93. Cell imaging with labeled fatty acids revealed a sharp alteration of the fatty acid flux with a reduced mitochondrial uptake. The other 35 discriminating lipids included phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamine, and sphingomyelins, mainly involved in membrane remodeling, and ceramides, gangliosides, and phosphatidylinositols, mainly involved in apoptotic cell signaling. Our results show that the inactivation of OPA1 severely affects the mitochondrial uptake of fatty acids and lipids through membrane remodeling and apoptotic cell signaling

Metabo-lipidomics of Fibroblasts and Mitochondrial-Endoplasmic Reticulum Extracts from ALS Patients Shows Alterations in Purine, Pyrimidine, Energetic, and Phospholipid Metabolisms

Amyotrophic lateral sclerosis (ALS) is characterized by a wide metabolic remodeling, as shown by recent metabolomics and lipidomics studies performed in samples from patient cohorts and experimental animal models. Here, we explored the metabolome and lipidome of fibroblasts from sporadic ALS patients (n = 13) comparatively to age- and sex-matched controls (n = 11), and the subcellular fraction containing the mitochondria and endoplasmic reticulum (mito-ER), given that mitochondrial dysfunctions and ER stress are important features of ALS patho-mechanisms. We also assessed the mitochondrial oxidative respiration and the mitochondrial genomic (mtDNA) sequence, although without yielding significant differences. Compared to controls, ALS fibroblasts did not exhibit a mitochondrial respiration defect nor an increased proportion of mitochondrial DNA mutations. In addition, non-targeted metabolomics and lipidomics analyses identified 124 and 127 metabolites, and 328 and 220 lipids in whole cells and the mito-ER fractions, respectively, along with partial least-squares-discriminant analysis (PLS-DA) models being systematically highly predictive of the disease. The most discriminant metabolomic features were the alteration of purine, pyrimidine, and energetic metabolisms, suggestive of oxidative stress and of pro-inflammatory status. The most important lipidomic feature in the mito-ER fraction was the disturbance of phosphatidylcholine PC (36:4p) levels, which we had previously reported in the cerebrospinal fluid of ALS patients and in the brain from an ALS mouse model. Thus, our results reveal that fibroblasts from sporadic ALS patients share common metabolic remodeling, consistent with other metabolic studies performed in ALS, opening perspectives for further exploration in this cellular model in ALS

Automatic ROI Selection in Structural Brain MRI Using SOM 3D Projection

This paper presents a method for selecting Regions of Interest (ROI) in brain Magnetic Resonance Imaging (MRI) for diagnostic purposes, using statistical learning and vector quantization techniques. The proposed method models the distribution of GM and WM tissues grouping the voxels belonging to each tissue in ROIs associated to a specific neurological disorder. Tissue distribution of normal and abnormal images is modelled by a Self-Organizing map (SOM), generating a set of representative prototypes, and the receptive field (RF) of each SOM prototype defines a ROI. Moreover, the proposed method computes the relative importance of each ROI by means of its discriminative power. The devised method has been assessed using 818 images from the Alzheimer's disease Neuroimaging Initiative (ADNI) which were previously segmented through Statistical Parametric Mapping (SPM). The proposed algorithm was used over these images to parcel ROIs associated to the Alzheimer's Disease (AD). Additionally, this method can be used to extract a reduced set of discriminative features for classification, since it compresses discriminative information contained in the brain. Voxels marked by ROIs which were computed using the proposed method, yield classification results up to 90% of accuracy for controls (CN) and Alzheimer's disease (AD) patients, and 84% of accuracy for Mild Cognitive Impairment (MCI) and AD patients.This work was partly supported by the MICINN under the TEC2012-34306 project and the Consejería de Innovación, Ciencia y Empresa (Junta de Andalucía, Spain) under the Excellence Projects P09-TIC-4530 and P11-TIC-7103. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRxResearch; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California

Population gene introgression and high genome plasticity for the zoonotic pathogen Streptococcus agalactiae

The influence that bacterial adaptation (or niche partitioning) within species has on gene spillover and transmission among bacteria populations occupying different niches is not well understood. Streptococcus agalactiae is an important bacterial pathogen that has a taxonomically diverse host range making it an excellent model system to study these processes. Here we analyze a global set of 901 genome sequences from nine diverse host species to advance our understanding of these processes. Bayesian clustering analysis delineated twelve major populations that closely aligned with niches. Comparative genomics revealed extensive gene gain/loss among populations and a large pan-genome of 9,527 genes, which remained open and was strongly partitioned among niches. As a result, the biochemical characteristics of eleven populations were highly distinctive (significantly enriched). Positive selection was detected and biochemical characteristics of the dispensable genes under selection were enriched in ten populations. Despite the strong gene partitioning, phylogenomics detected gene spillover. In particular, tetracycline resistance (which likely evolved in the human-associated population) from humans to bovine, canines, seals, and fish, demonstrating how a gene selected in one host can ultimately be transmitted into another, and biased transmission from humans to bovines was confirmed with a Bayesian migration analysis. Our findings show high bacterial genome plasticity acting in balance with selection pressure from distinct functional requirements of niches that is associated with an extensive and highly partitioned dispensable genome, likely facilitating continued and expansive adaptation