dataesr/scientific-paragraphs-categorization huggingface dataset:
3B, C ). Our Pb data overlap those from the literature  (Hedge et al. , 1973; Mahoney et al. , 1996; Salters and White, 1998; Zhou, 1996)   3B, C ). The two groups of islands are also distinct in He isotopic compositions: the East and Possession lavas have less primitive R/R a (8. 2±1. 2, N = 5w i t hR/R a = 3 He/ 4 He sample / 3 He/ 4 He atmosphere ) than those of Penguins (13. 4 ± 0. 5, N = 3). The high Penguins Island ratios are similar to those of the Reunion Island (R/R a be- (1) He isotopes were measured on olivine. See Material and methods section for details. tween 11. 5 and 13. 3,  Graham et al. , 1990; Hopp and Trieloff, 2005 , and references therein) or other plumes with deep-mantle origin, like Hawaii or the Galapagos Islands  (Farley and Neroda, 1998; Hofmann et al. , 2011, and references therein).
4A, B )). Details concerning the PCA are provided in Appendix A3. In the literature, the source materials of magmas are often referred to as component as are   1 ) and from the literature (G i r e te ta l. ,2 0 0 2 ;  Mahoney et al. , 1996; Zhou, 1996). Error bars are smaller than the symbols. SWIR MORB data are from the PetDB database (http://www. petdb. org/). Data for the Kerguelen, Comoros, Reunion and Mauritius Islands are from the GeoROC database (http://georoc. mpch-mainz. gwdg. de/)( r e f e r e n c e sa r el i s t e di nA p p e n d i xA 4 ). D a t a for the Marion Island are from the GeoROC database and Le  Roex et al. (2012). T h e FOZO fields are drawn after  Stracke et al. (2005). No renormalization of the Pb data was performed because the effect would be insignificant compared to the overall dispersion of the data.
Pb isotopes plots to determine the three mantle sources involved in Crozet (Fig. 5 ). The results in both the 87 Sr/ 86 Sr vs. 206 Pb/ 204 Pb and 143 Nd/ 144 Nd vs. 206 Pb/ 204 Pb spaces are similar to those of the PCA on Pb isotopes: the Crozet lavas form two main groups, one with the East and Possession Island samples and the other with the Penguins Island samples. Our new East and Possession Island isotopic data plot within the field defined previously by  Mahoney et al. (1996)  and  Zhou (1996)  (Fig. 5 ). Our new data show that Penguins Island lava form a distinct group with lower 87 Sr/ 86 Sr, higher 206 Pb/ 204 Pb, and higher 143 Nd/ 144 Nd than the East and Possession group. Thus, the Crozet plume appears to sample several mantle sources similar to what is ob- served for the Hawaii hotspot for example  (Abouchami et al.
5 ). The samples plot between the FOZO field and a field defined by SWIR MORBs. We interpret this trend as reflecting a mixing between the FOZO-like source and a Depleted MORB Mantle (DMM) end-member. Our new data on the Penguins Island show that three mantle sources are required to explain the geochemical variations within the Crozet hotspot. Two of them are sampled in large proportions in the Crozet lavas: a FOZO-like component and an E-P (Reunionlike) component. These components are heterogeneously sampled within the Crozet Archipelago. The eastern islands, East and Possession, preferentially sample the E-P component, whereas Penguins Island mainly samples the FOZO component. The scatter in the data is caused by the contribution of a third component, which is likely to be the local DMM.
Data for the SWIR are from PetDB (references listed in Appendix A4). Isotope variability within plume products was also observed in other plumes, like Hawaii for example, and sometimes enabled to understand the plume structure and its temporal evolution  (Abouchami et al. , 2000; Blichert-Toft and Albarède, 2009; Eisele et al. , 2003; Fekiacova et al. , 2007). We did not perform such an investigation in regard of the limited dataset and the absence of clear temporal relationships between our samples.
Acknowledgements We thank the  French Polar Institute  ( IPEV-DyLioker 444 program ) for their support for the sampling, and  R. Bellec ,  N. Leviavant  and  H. Perau  ( IPEV staff ) for their assistance in the field. We also thank  A. Giret  and the  French Polar Rocks Collection  at the  Jean Monnet University (Saint-Etienne, France)  who provided the samples from Penguins and East Islands. We thank  J. -L. Devidal  for support during EMP analysis,  C. Douchet ,  E. Albalat ,  F. Arnaud-Godet , and  P. Telouk  for maintaining the clean lab and ICP-MS facilities in Lyon in state-of-the-art working conditions. We thank  P. Bowden ,  G. Quitté  and  K. T. Koga  who kindly accepted to proofread early versions of the manuscript. Thoughtful and constructive reviews by  Andreas Stracke  and three anonymous reviewers improved the manuscript considerably.
Cells were incubated with 5-ethynyl-2′-deoxyuridine (EdU) (30 lmol/L) from Invitrogen (Carlsbad, CA) for 6 h, and then washed twice with PBS and fixed with 4% paraformaldehyde. Cells were permeabilized with 0. 1% Triton-X 100 in PBS for 5 min, then incubated with 5% normal donkey serum-blocking buffer for 2 h. Incorporated EdU was detected with a copper-catalyzed fluorescent azide reaction (Click-iT; Invitrogen), after which slides were washed with PBS and mounted on cover slips with mounting medium containing 4′,6-diamidino-2-phenylindole (DAPI) (Vector, Burlingame, CA). Nuclei and EdU-positive nuclei were counted using the (209/0. 8 NA) air objective of an Axio Observer. Z1 fluorescence microscope (Zeiss, Germany) with Metamorph software (Molecular Devices, CA).
Confocal laser scanning microscopy ENPs were conjugated with Nile red (nominal diameter = 73 nm, zeta potential = +47, and polydispersity index = 0. 34) according to a method described previously  (Yoo et al. 2011). Nuclei were stained with Hoechst 33342 (Sigma, ST. Louis, MO), mitochondria were stained with MitoTracker Deep Red 633 (Invitrogen/Molecular Probes, Eugene, OR), and the membranes were stained with Wheat Germ Agglutinin Alexa Fluor 488 conjugate, WGA (Invitrogen). Cells were observed with a (209/1. 0 NA) water-dipping objective in a Zeiss LSM 780 microscope. A three-dimensional (3D) movie of HMEC 184 cells incubated for 3 days with Nile red-ENPs was generated using Imaris software (Bitplane, Zurich, Switzerland). ImageJ software was used to find ENPs localized with mitochondria (Wayne Rasband, NIH, Bethesda, MD).
A total of 178 proteins were identified and analyzed for name of product in B. taurus (as they appeared in Unigene (http://www. ncbi. nlm. nih. gov/UniGene/), name of gene in Homo sapiens counterpart, name of human counterpart protein (http://www. uniprot. org/uniprot/), and plasma levels in human and InterPro domains if applicable (http:// www. genecards. org/). A total of 69 proteins were cited only by their B. taurus name and were not included in data analysis because either (i) their relative abundance (RA) was very low (1-10), (ii) their identified peptides span less than 3% of the protein sequence, or (iii) they were isoforms of, or closely related to, already analyzed proteins. Proteins were ranked according to their (i) abundance (A), namely the ratio of spectrum count/length, and (ii) sequence coverage (SC), namely the percentage of the entire sequence that was expressed in the peptides found in trypsin hydrolysate.
Total RNA extraction and microarray analysis Total RNA was extracted from HMEC 184 cells (50% and 90% confluence) incubated with 25 lg/mL ENPs for 24 h, and without incubation (control). The quality of RNA extracted with RiboPure kit (Ambion, Austin, TX) was determined with spectrophotometry and capillary electrophoresis, using RNA 6000 Nano â (Agilent 2100 Bioanalyser TM , Santa Clara, CA). cDNA synthesis, cRNA synthesis, Cy3-dye labeling, and microarray hybridization were carried out using 100 ng of total RNA according to manufacturer protocol (One-Color Microarray-Based Gene Expression Analysis, version 6. 6). Microarray slides (Sure-Print G3 Human GE v2 8x60K, Agilent technologies) were scanned with an Agilent DNA microarray scanner. The acquisition, quantification of array images, and primary data analysis were performed using Agilent Feature Extraction Software.
Data were first normalized with quantile method and stringent filtering criteria were next used to identify genes whose expression level was significantly changed, with a modified Student's t-test (P ≤ 0. 001) and FC (fold change) ≥2. 0. FC of mean of three replicates (for each ENP exposure and cell condition) on control were calculated. The selected genes display acceptable false discovery rate (<15%) according to  Benjamini et al. (2001). The Database for Annotation, Visualization, and Integrated Discovery (DAVID; http://david. abcc. ncifcrf. gov) was then used to analyze and extract (i) relevant GO terms (http:// godatabase. org), (ii) functions and expression data on Genecard (http://www. genecards. org), and (iii) known and predicted protein-protein interactions (http://string-db. org) for selected genes (da  Huang et al.
3  and 2013 | Vol. 1 | Iss. 4 | e00027 Movie S1), but the majority of ENPs aggregated into clumps with proteins that formed a clearly visible network closely attached to cells. Colocalization analysis in ImageJ showed that some ENPs are localized with mitochondria (Fig. 3G ). No fragmentation was seen in mitochondrial networks in HMEC 184, MDA-MB-231, and MCF-7 cells treated with ENPs at 25 lg/mL for 24 and 72 h (data not shown). There was an increase in the total mitochondrial volume in HMEC 184 cells treated with 25 lg/mL ENPs, when compared with untreated control cells as measured with Imaris software (Fig. 4A ). However, a decrease in Cox4 and VDAC proteins was seen with Western blotting, but neither was a significant change (Fig. 4B ). This implies an increase in cell size without a corresponding increase in mitochondrial biogenesis.
Proteomic MS showed that the ENP-serum protein network contains proteins sharing common InterPro domains and exhibiting protease, antiprotease, epidermal growth factor, adhesion, and binding properties To identify the nature of the visible flocculate, the pellet generated from centrifugation of a mixture of serum and ENPs was washed twice with PBS and exposed to organic extraction. No lipids were seen in the organic phase on TLC, but the aqueous phase showed a peak at 280 nm and an increased absorbance at 240 nm, with the UV/VIS spectrum suggesting the presence of proteins (data not shown). The pellet was examined with SDS-PAGE and MALDI-TOF MS, which identified 290 nonredundant proteins belonging to B. taurus and nine human cytokeratins. From MALDI-TOF MS, 178 proteins were identified and analyzed.
The most frequently shared InterPro domain was "IPR006210:EGF-like," shared by 18 different proteins (Table  1 ). Approximately 120 (70%) of 170 analyzed proteins shared at least two common domains. A high number of proteins belonging to InterPro domains are known to be involved in endopeptidase inhibitor activity, proteolytic activity or its regulation, protein binding, calcium binding, cell adhesion, and signaling, or have certain structural motifs like leucine-rich or immunoglobulin domains (Table  1 ). By calculating the mean of RA at the domain level, but not at the entire protein level, we found that proteins were coated not only due to their relative amounts in FBS but also due to their affinities for ENPs, reflecting their composition in domains rather than the structure of the entire protein (Table  1A ).
When submitting 178 genes to the STRING database, 169 protein encoding genes were recognized, and more than 80% of these showed interactions, either at evidence, confidence, or action levels. Seemingly, the purified proteins were also isolated by interactions between and among themselves (e. g. , by protease inhibitor/protease interactions, or known binding properties of individual proteins). Serpins, proteases, and coagulation factors were found at the central core around which proteins involved in cell adhesion, growth, differentiation, and migration clustered (Fig. A4 ). Microarray analysis for HMEC 184 cells treated with 25 lg/mL ENPs showed activation of proliferation and growth pathways Microarray analysis was performed on HMEC 184 treated cells to identify the pathways induced by ENP treatment.
InterPro Name Number macrophage functions involved in endocytosis and potentializing MARCO. Some of the induced genes code products that use proteins adsorbed on ENP as substrate, such as MMP8, MMP9, and LCN2, all of which activate procollagenase, and cleave collagene IV and VI, which bind to ENP. MMP9 and SERPINB2 degrade fibronectin and vitronectin, both adsorbed on ENP. KK6 displayed hydrolytic activity against extracellular matrix proteins adsorbed on ENP, such as fibronectin, laminin, vitronectin, and collagen. Forty-one of the 84 genes in the 90% confluence series recognized by the STRING database (http://string-db. org) were linked at confidence, evidence, or action level (Fig. 5 ). Regarding the action level, some relevant CAPN14 CAPN14 CAPN14 MUC16 MUC16 MUC16 KRT80 KRT80 KRT80 RTKN2 RTKN2 RTKN2 KIF13B KIF13B KIF13B CEACAM1 CEACAM1 CEACAM1 MACC1 MACC1 MACC1 CHST6 CHST6 CHST6 HPGD HPGD HPGD NLRP10 NLRP10 NLRP10 SPON2 SPON2 SPON2 RASSF3 RASSF3 RASSF3 MAL2 MAL2 MAL2 CEACAM6 CEACAM6 CEACAM6 ERBB3 ERBB3 ERBB3 MALL MALL MALL B3GALT4 B3GALT4 B3GALT4 KRT34 KRT34 KRT34 DGAT2 DGAT2 DGAT2 MAP2 MAP2 MAP2 HMOX1 HMOX1 HMOX1 MYO5B MYO5B MYO5B CAPN5 CAPN5 CAPN5 CDKN1C CDKN1C CDKN1C RAB11FIP1 RAB11FIP1 RAB11FIP1 BNIPL BNIPL BNIPL PLA2G7 PLA2G7 PLA2G7 AGPAT9 AGPAT9 AGPAT9 LCN2 LCN2 LCN2 SAA3P SAA3P SAA3P IGFL2 IGFL2 IGFL2 PLA2G4D PLA2G4D PLA2G4D IL1RN IL1RN IL1RN PCDH1 PCDH1 PCDH1 CWH43 CWH43 CWH43 PRR15L PRR15L PRR15L ANXA1 ANXA1 ANXA1 IL8 IL8 IL8 SERPINB2 SERPINB2 SERPINB2 S100P S100P S100P B3GNT3 B3GNT3 B3GNT3 MMP10 MMP10 MMP10 MMP1 MMP1 MMP1 KRT23 KRT23 KRT23 MMP9 MMP9 MMP9 OVOL1 OVOL1 OVOL1 MARCKSL1 MARCKSL1 MARCKSL1 FA2H FA2H FA2H FUT2 FUT2 FUT2 FUT3 FUT3 FUT3 MAPRE2 MAPRE2 MAPRE2 TLR2 TLR2 TLR2 OASL OASL OASL ISG20 ISG20 ISG20 ELF3 ELF3 ELF3 ADAM8 ADAM8 ADAM8 LIPH LIPH LIPH TLR1 TLR1 TLR1 NDRG2 NDRG2 NDRG2 CLDN4 CLDN4 CLDN4 NCF2 NCF2 NCF2 HOPX HOPX HOPX RARRES1 RARRES1 RARRES1 CLDN7 CLDN7 CLDN7 PLBD1 PLBD1 PLBD1 CGN CGN CGN KRT24 KRT24 KRT24 DSG4 DSG4 DSG4 CLDN3 CLDN3 CLDN3 ATP12A ATP12A ATP12A GUCY1A3 GUCY1A3 GUCY1A3 S100A12 S100A12 S100A12 MARCO MARCO MARCO APCDD1 APCDD1 APCDD1 PIM1 PIM1 PIM1 VTCN1 VTCN1 VTCN1 ELOVL4 ELOVL4 ELOVL4 CYP4B1 CYP4B1 CYP4B1 GGT6 GGT6 GGT6 CDSN CDSN CDSN KLK6 KLK6 KLK6 FLG FLG FLG SPINK5 SPINK5 SPINK5 S100A7 S100A7 S100A7 Figure  5.
Protein-protein interactions of 84 overexpressed genes in HMEC 184 cells, as retrieved from String database. HMEC 184 cells (90% confluence) were incubated with and without 25 lg/mL ENPs for 24 h. Total RNA was extracted and analyzed with microarray. There were 287 genes whose expression was significantly altered when compared control. Forty-one of 84 genes recognized by String database were linked at the confidence, evidence, or action level. 2013 | Vol. 1 | Iss. 4 | e00027 catalysis involve: (i) initial activation of proMMP9 by MMP1, (ii) proMMP-9 activation by MMP-10, (iii) CEA-CAM1&6 heterodimer, (iv) MMP9 potentializing IL8, and (v) complex forming of serum amyloid A protein with upregulated TLR genes, SAA1/TLR2/TLR1.
Acknowledgments We thank  Gary Firestone ,  Martha Stampfer , and  James Garbe  for their gifts of epithelial cell lines. We thank  Alain Le Faou  for his comments on our manuscript. Images were taken at the  Molecular Imaging Center facility  in the  Cancer Research Laboratory at UC Berkeley. MALDI-TOF mass spectrometry analysis was performed at the proteomic mass spectrometry laboratory under direction of  Lori Kohlstaedt  at  UC Berkeley. We thank our students  Maxine Nanthavong, Ph edre Rihn , and  Tabya Sultan  for their help.
It is necessary to identify molecular markers that predict doxycycline resistance or decreased susceptibility in order that active surveillance can monitor temporal trends in parasite susceptibility  [9]. Although there have been no reported clinical failures for the treatment of falciparum malaria with doxycycline, a Bayesian mixture modelling approach has distinguished three different in vitro phenotypic groups: low, medium and high doxycycline IC 50 values, among 747 P. falciparum isolates obtained from 14 African countries over a nine-year period  [10]. The sequences of 11 P. falciparum genes that are analogous to those involved in bacterial resistance to doxycycline were obtained from 30 isolates from each phenotypic group. The data suggested that the copy numbers of a tetQ GTPase family gene, pftetQ (PFL1710c), and a metabolic drug transporter gene, pfmdt (PFE0825w), were potential molecular markers of decreased in vitro susceptibility to doxycycline in African isolates  [11].
Patients and sample collection Between January 2006 and December 2010, 484 fresh P. falciparum isolates were obtained at the French National Reference Centre for Imported Malaria (Paris) from patients hospitalized with malaria after having returned to France. These samples were successfully assessed for doxycycline susceptibility. Ex vivo testing of doxycycline susceptibility was performed as previously described by a standard 42-hour 3 H-hypoxanthine uptake inhibition assay  [12]. Batches of plates were tested and validated on the chloroquine-susceptible 3D7 strain and the chloroquineresistant W2 strain. The drug concentration that inhibited 50% parasite growth (IC 50 ) was calculated with the inhibitory sigmoid Emax model, with estimation of the IC 50 through nonlinear regression using a standard function of the R software (ICEstimator)  [13].
Quantification of pftetQ and pfmdt copy numbers pfmdt (PFE0825w) and pftetQ (PFL1710c) copy numbers were estimated by TaqMan real-time PCR (7900HT Fast Real-Time PCR system, Applied Biosystems) relative to the single-copy gene, pfβtubulin (PF10_0084). The following oligonucleotide primers and probes were designed using the Primer Express software v2. 0 (Applied Biosystems) for use in the polymerase chain reactions (PCRs): 5′-TTATGCAAACATTTCAAGCTTCCT-3′, 5′-ACCC ATTCCATAACTTAGATTTAGATAACC-3′ and 5′-VIC-TAAAAACAAATTTCGACAAAAGGACAGGAGCC-TA MRA-3′ for pfmdt, 5′-ACCCCTTTTTTATCTTACGAA AG-3′, 5′-ATGGTTGTACGTTATATCATATGG-3′ and 5′-VIC-AAAAATGTGGCAACAATTCAGACATGTATC A-TAMRA-3′ for pftetQ and 5′-TGATGTGCGCAAGT-GATCC-3′, 5′-TCCTTTGTG GACATTCTTCCTC-3′ and 5′-FAM-TAGCACATGCCGTTAAATATCTTCCAT GTCT-TAMRA-3′ for pfβtubulin (Eurogentec).
Individual PCRs were performed using 1 X TaqMan Universal PCR Master Mix (Applied Biosystems), 900 nM forward primer, 900 nM reverse primer, 250 nM TaqMan probe and 5 μL template DNA in a final volume of 25 μL The reaction mixtures were prepared at 4°C in a 96-well optical reaction plate (Applied Biosystems) covered with optical adhesive covers (Applied Biosystems). The thermal cycling conditions were 50°C for 2 min, 95°C for 10 min and 50 cycles of 95°C for 15 sec and 60°C for 1 min. Each sample was assayed in triplicate and analysed with the SDS software 2. 2. 1 (Applied Biosystems). The PCR efficiencies of all the primer pairs were evaluated on a dilution series of P. falciparum 3D7 genomic DNA. The efficiencies were found to be sufficiently close to obviate the need for any correction factor.
Results The doxycycline IC 50 values ranged from 0. 49 to 65. 1 μM. The mean was 11. 64 μM (95% confidence interval, 10. 96-12. 33). The average parameter estimates for the IC 50 values by year are given in Table  1. The triple normal distribution model is represented in Figure  1. The parameter estimates for the three-component mixture model, including the number of isolates in each normal distribution, the mean of the IC 50 values and the standard deviation for each distribution, are summarised in Table  2. A double normal distribution model and a quadruple normal distribution model were also fitted to the data to assess the validity of considering a three-component mixture (data not shown). These two models fit the data worse than the triple normal distribution model. Eighty-nine P. falciparum isolates (30, 30 and 29) were randomly chosen from the three phenotypic groups, A, B and C, that differed in their doxycycline IC 50 values.
The ambient light was then turned off (0 cd/m 2 ), and the patient was dark-adapted for 1 min prior to the pupil recording session. Thereafter the continuous recording was initiated: during the first 10 s in darkness, a mean baseline pupil diameter was calculated, in order to normalize pupil size readings (See Data normalization and processing). Thereafter a continuous 20 s light stimulus (either blue or red light) was presented, and the pupil dynamics were recorded during the illumination and 1 min after light termination. The light stimulation protocol was standardized, stimulation with red light being followed by stimulation with blue light. A 3min pause in mesopic light separated two successive recordings (i. e. , red light test from blue light test), followed by a 1-min adaptation in prestimulus darkness before the next recording.
MAIN OUTCOME PARAMETERS The maximal pupil contraction amplitude (maximal CA) was determined at the maximal contraction point within the first 6 s during illumination. This parameter reflected outer photoreceptor function  (McDougal and Gamlin, 2010; Gooley et al. , 2012). The maximal CA was calculated as the mean of three data points and reported as the maximal difference (expressed as %) from the baseline.
STATISTICAL ANALYSIS Statistical Analysis System (SAS) software (SAS version 9. 2, SAS Institute Inc. , Cary, NC, USA) was used for statistical analysis. Data was analyzed using a linear model, including the darkadapted pupil diameter in absolute values (mm), gender and age as covariates, and outcome parameters were adjusted by the Tukey-Crammer method for multiple comparisons. Due to a small sample size, the main outcome results were also confirmed with non-parametric tests. A p-value < 0. 05 was considered significant for all tests. For calculations of visual acuity, ETDRS units were used and converted to decimal equivalents in tables for easy overview.
THE DARK-ADAPTED (BASELINE) PUPIL DIAMETER The dark-adapted (baseline) pupil diameter (mm) was recorded prior to each test session. The mean dark-adapted (baseline) pupil size of the affected eyes was 6. 37 mm (95% CI: 5. 15-7. 59 mm), and in the fellow non-affected eyes it was 6. 43 mm (95% CI: 5. 45-7. 42 mm). The mean of the healthy control eyes was 7. 03 mm (95% CI: 6. 46-7. 60 mm). There was no significant difference between the baseline pupil diameters in the three groups (p = 0. 43). Moreover, in our study, the main outcome parameters were not influenced by the BS (data analyzed with linear models).
ACKNOWLEDGMENTS The authors would like to thank inventor  Palle R. Jensen  for constructing the color pupillometer, and senior scientist  Ph. D. Birgitte Thestrup  and associate professor  Beata Kardynal  ( Technical University of Denmark, Department of Photonics Engineering ) for technical assistance on safety issues. Grant information: the project was supported by  The VELUX Foundation ,  The John  and  Birthe Meyer Foundation , the  University of Copenhagen  ( SUNDs Institutstipendium ), The  Danish Eye Health Society  ( Øjenforeningen Vaern om Synet ), The  Danish Eye Research Foundation (Øjenfonden) ,  Danish Research Council , and  UNADEV (Union Nationale des Aveugles et Déficients Visuels), France.