dataesr/scientific-paragraphs-categorization huggingface dataset:
2A ). The functional classification of these proteins showed a wide distribution of activities (Fig. 2B ). Changes of the Luminal Proteomes Along the Estrous Cycle-Proteomic quantification was performed to assess the effect of the cycle stage (estrus versus luteal phase) and the type of cycle (spontaneous vs. synchronized) on the abundance of proteins in the various fluids of the female tract (cervix, uterus, and oviduct). A total of 694 proteins were identified by GeLC-MS/MS and the data are summarized in the supplemental Table  S2. Proteins were considered significantly differentially abundant between estrus and luteal   S3  (cervix, spontaneous and synchronized estrus), supplemental Table  S4  (uterus, spontaneous and synchronized estrus), and supplemental Table  S5  (oviduct, spontaneous and synchronized estrus).
Acknowledgments-We thank  Damien Capo  and the  INRA Experimental Farm (UEPAO). We thank  Olivier Sandra  and  Marie Saint-Dizier  for their comments on the manuscript. *This work was supported by various grants. P. Kohnke was supported by a post-doctoral fund provided by the  French Agence Nationale de la Recherche. SP de Graaf  is supported by  Australian Wool Innovation  and the  NSW Stud Merino Breeders Association Trust. The high resolution mass spectrometer was financed ( SMHART  project) by the  European Regional Development Fund (ERDF) , the  Conseil Regional du Centre , the  French National Institute for Agricultural Research (INRA)  and the  French National Institute of Health and Medical Research (Inserm). □ S This article contains supplemental Tables  S1  to S7. ¶ ¶ To  whom correspondence should be addressed:  UMR INRA 85 ,  CNRS 7247-UniversiteFrancois Rabelais-IFCE, Unitede Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, Centre de Recherches Val de Loire, 37380 Nouzilly, France.
Although one residual appeared greater than the others (Fig  3a ), Grubbs' test applied to the residuals did not indicate any outlier. Wild lions may occasionally live longer than 13 years, however by 10 years of age, most wild lions have severe wear or breakage of teeth  [21, 22]. Crown damage that results in pulpal exposure can permanently halt dentine formation  [21]. The linear regression formula provided a good fit through our dataset which included three (captive) lions 13 years of age. Thus, our model is applicable to lions up to the age of 13 years, perhaps older, provided that intact PM 2 s are available for X-ray analysis and measure. Smuts et al. (1978)  reported that the pulp chamber in lion canines never becomes completely obliterated. Similarly, all three of the 13-year-old lions in this study retained a small opening of the pulp chamber visible on X-ray, suggesting that complete ossification of the PM 2 may not occur in African lions, or not in all individuals.
Specifically, Smuts et al. (  1978 ) examined pulp closure rates by measuring maximum pulp width in canines, on a dataset that included cubs. In contrast, our study measured total pulp/tooth areas in PM 2 s, and did not include lions under 3 years of age. Differences in morphology and developmental chronology between lion canine and PM 2 teeth are vast. Thus, caution should be used when comparing characteristics of pulp chamber closure between studies. While our findings suggest that ROAR may be broadly applicable to other lion populations, additional work is needed. In particular, continued testing of this regression formula to PM 2 s of known-aged lions from other populations and geographic regions is required to verify the accuracy of this method as a widespread tool. Increasing the sample size, especially in the 4-6-year-old age range that is of key importance to age-based trophy selection programs, and including lions older than 13 years would be prudent, and may allow further refinement of the model.
Data Collection Tooth X-rays were obtained from cleaned lion skulls in South Africa (n = 25) and from live lions (n = 6) and skulls (n = 2) in Tanzania. South African lions were born in captivity and thus, their exact birth dates were known. Skulls of South African lions were examined and teeth X-rayed on-site at taxidermy studios. Age data on captive lions were obtained from the husbandry records kept by licensed animal-holding facilities in accordance with South Africa's permitting requirements for Threatened and Protected Species (TOPS)  [38]  S2 Text. In Tanzania, the ages of wild-living lions were known from long-term behavioural studies in Serengeti National Park  [39]  in which individuals were photographed at birth and thereafter identified and monitored over time using whisker spot patterns  [40].
Acknowledgments We thank the  South African Predator Association  for their assistance in obtaining data on known-aged lions and taxidermy studios in South Africa for providing access to lion skulls. We thank  Tanzania Wildlife Research Institute, Commission for Science and Technology (COST-ECH)  and  Tanzania National Parks  for permission to carry out the study in Tanzania. We are grateful to  Dr. Eblate  of  TAWIRI  for veterinary services,  Z. Zumo  for assistance in field X-raying, and  Serengeti Lion Project personnel  ( S. Mwampeta ,  D. Sorgein  and  C. Packer ) for assistance in identification and field tracking of known-age lions.
To estimate the odds ratio of Parkinson's disease in 22q11. 2 deletion carriers, we assumed a population prevalence of 22q11. 2 deletions of 0•024%,  23  which is close to 25 in 100 000 livebirths. 9 One-sided p value was also added in footnotes of result tables to enable readers who wish to compare with some previous CNV studies using one-sided test. We did all statistical analyses in SPSS (version 20. 0. 0) and R (version 3. 12). p values of 0•05 or lower were judged to be statistically signifi cant.
Results 9387 patients with Parkinson's disease and 13 863 controls were included from the four case-control studies. The disease age at onset was available for 8451 (90%) of 9387 patients with Parkinson's disease. Age at onset data were available for all patients carrying the 22q11. 2 deletion. The most common deletion associated with chromosome 22q11. 2 deletion syndrome spans about 3 Mb (around hg19 chromosome 22: 18•8-21•8 Mb) and is fl anked by LCRs A-D (fi gure). We identifi ed eight unrelated patients with Parkinson's disease who carried the most common chromosome 22q11. 2 deletion syndrome (3 Mb) deletion from three independent Parkinson's disease studies, with none detected in the fourth, smallest study (US NIA; fi gure; table  1 ). Using the customised CytoSure 15k-Array, we validated all the 3 Mb deletions in the UK groups (UK 1 and UK 2, data not shown).
These data confi rmed the deletion breakpoint fi ndings from the Illumina array. We did not replicate the validation in other studies because the validation in UK samples showed convincing results using the Illumina array. Analysis of the largest independent study (UK WTCCC2, assuming the IPDGC NeuroX study is a metaanalysis of studies) revealed a pattern of enrichment of 22q11. 2 deletion in patients with Parkinson's disease (p=0•059; table 1). A similar pattern was noted when the IPDGC NeuroX study was classed as a homogeneous study, using the Fisher's exact test (table  1 ). In the combined meta-analyses of all independent samples (9387 patients with Parkinson's disease and 13 863 controls; table 1), 22q11. 2 deletions were associated with Parkinson's disease, both when the IPDCG NeuroX study was classed as one subgroup (four-subgroup analysis p=0•00056) and when each group within that study was classed as a separate subgroup (ten-subgroup analysis; p=0•00082).
2 deletions. Post hoc, we attempted an The eight patients fulfi lled the UK Brain Bank Criteria for Parkinson's disease, had asymmetry in onset of motor symptoms and tremor (seven of seven patients with assessment records available), developed bradykinesia and rigidity during the disease course (six of six patients with available data), and most had a good initial response to levodopa or dopamine agonist treatment (fi ve of six). No structural abnormalities were noted in all three patients for whom MRI scan data were available (IPDGC NeuroX 4 and 5, and UK 1). Dopamine transporter scans were abnormal in all four patients for whom these data were available, with asymmetric defi cits in two (UK So far, no data exist on the prevalence of chromosome 22q11. 2 deletion syndrome in Parkinson's disease.
2 deletion carriers should be addressed in future studies. Contributors KYM, US, AYA, VP, NMW, and NWW designed the study. KYM, US, JS-S, AS, LC, VE-P, and KM analysed the data and prepared and revised the manuscript. JS-S, KMD, AJN, NEM, SJL, CHW-G, RAB, KDvD, HWB, PH, J-CC, FC, SL, AB, KB, CS, TG, TF, PL, KEM, CEC, SS, TTW, AJL, HRM, MAN, ABS, and JH collected the original samples, clinical information, and genetic data, and discussed and revised the manuscript. The IPDGC collected the samples. AYA, VP, NMW, and NWW supervised the study.
Acknowledgments This work was supported fi nancially by a  Medical Research Council (MRC)  and  Wellcome Trust   Strategic Award  ( WT089698/Z/09/Z ) to the  UK Parkinson's Disease Consortium , whose members are from the  UCL Institute of Neurology, University of Sheffi  eld, and the  MRC Protein Phosphorylation Unit at the University of Dundee ; and a grant from the  Karin och Sten Morstedt CBD Solutions AB. The work was undertaken at  University College London Hospitals  and  University College London , who receive support from the  Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centres  funding streams. This work was also supported by a  Parkinson's UK  project grant ( G1309 ) and a studentship from the  Saudi Cultural Bureau  ( Ref 15600 ). KYM was partly supported by  ERA-Net NEURON  and is supported by a grant from the  Karin och Sten Mortstedt CBD Solutions AB.
AS has received grants from the  Saudi Cultural Bureau. VE-P, KM, and AJN have received grants from  Parkinson's UK. SJL, HRM, and  NMW , are funded by  Parkinson's UK  (Grants  8047  and  J-1101 ) and the  MRC UK  ( G0700943 ,  G1100643 ). HRM has also received grants from the  MRC UK , the  Welsh Assembly Government , the  Motor Neurone Disease Association , the  PSP Association , and the  Drake Foundation. CHW-G has received a clinical research fellowship from the  Patrick Berthoud Trust ; an  NIHR Biomedical Research Centre  award to the  University of Cambridge, Cambridge University Hospitals NHS Trust ; grants from the  MRC ,  Wellcome Trust ,  Parkinson's UK , the  Rosetrees Trust ,  Academy of Medical Sciences, and Addenbrooke's Charitable Trust ; and travel expenses and faculty stipend from the  Movement Disorder Society.
KDvD and HWB have received grants from the  Dutch Parkinson Foundation  ( Parkinson Vereniging ) and  Neuroscience Campus Amsterdam. J-CC  has received grants from  Agence Nationale pour la Recherche  ( ANR-10-IAIHU-06 ), the  French Ministry of Health , and the  Michael J Fox Foundation. KB has received grants from the  University of Tübingen , the  German Society of Parkinson's disease , and the  Michael J Fox Foundation. AJL has received grants from the  PSP Association , The  Reta Lila Weston Trust , and  The Reta Lila Howard Foundation. KEM has received support from the  MRC  and  NIHR. ABS has received support from the  Intramural Research Program of the National Institute on Aging, National Institutes of Health , a part of the  Department of Health and Human Services  ( ZO1 AG000949 ).
Herpes simplex virus type 1 (HSV-1) is a neurotropic virus linked to a range of acute and chronic neurological disorders affecting distinct regions of the brain. Unusually, HSV-1 entry into cells requires the interaction of viral proteins glycoprotein D (gD) and glycoprotein B (gB) with distinct cellular receptor proteins. Several different gD and gB receptors have been identified, including TNFRSF14/HVEM and PVRL1/nectin 1 as gD receptors and PILRA, MAG, and MYH9 as gB receptors. We investigated the expression of these receptor molecules in different areas of the adult and developing human brain using online transcriptome databases. Whereas all HSV-1 receptors showed distinct expression patterns in different brain areas, the Allan Brain Atlas (ABA) reported increased expression of both gD and gB receptors in the hippocampus.
Specifically, for PVRL1, TNFRFS14, and MYH9, the differential z scores for hippocampal expression, a measure of relative levels of increased expression, rose to 2. 9, 2. 9, and 2. 5, respectively, comparable to the z score for the archetypical hippocampus-enriched mineralocorticoid receptor (NR3C2, z = 3. 1). These data were confirmed at the Human Brain Transcriptome (HBT) database, but HBT data indicate that MAG expression is also enriched in hippocampus. The HBT database allowed the developmental pattern of expression to be investigated; we report that all HSV1 receptors markedly increase in expression levels between gestation and the postnatal/adult periods. These results suggest that differential receptor expression levels of several HSV-1 gD and gB receptors in the adult hippocampus are likely to underlie the susceptibility of this brain region to HSV-1 infection.
However, no studies have addressed the expression of HSV-1 receptors other than PVRL1 in human brain. In mice, there are marked changes in receptor expression between the fetal and postnatal periods  (Horvath et al. 2006; Prandovszky et al. 2008 ), but the patterns of HSV-1 receptor expression in adult human brain have not been examined. We therefore used different online transcriptome databases to map the expression patterns of all known HSV-1 gD and gB receptors in adult and developing human brain.
Extraction of expression profiling data Expression profiling results were first extracted from the microarray-based Allen Human Brain Atlas (ABA; v. 1 March 2013; brainmap. org) of human brain gene expression  (Hawrylycz et al. 2012 ) using the syntax GENE1 OR GENE2. The database is generally based on at least two probes per gene and brain samples from six individuals. The ABA heatmap image was toggled to align all results by region; the image and associated z score data were downloaded. To evaluate fold changes in expression levels, the ABA human gene database was interrogated in differential mode for Hpc versus a control brain tissue, cerebellum. For developmental expression profiling, the microarray-based Human Brain Transcriptome database (consulted August 2016; http://hbatlas. org/pages/hbtd) was employed.
Expression in adult human brain Currently, both glycoprotein D (gD) and group glycoprotein B (gB) receptors are known to be essential for HSV-1 viral entry (Table  1 ). To address their distribution in adult human brain, we extracted the expression profiles as z scores (see BMethods^section) from the microarray-based Allen Brain Atlas (ABA) gene expression database of adult human brain  (Hawrylycz et al. 2012). Controls were housekeeping gene GAPDH and the Hpc-selective gene NR2C3 (mineralocorticoid receptor). In Fig. 1a , the z scores for HSV-1 gD and gB receptors are plotted across the human brain, and Fig. 1b  shows their distribution in the telencephalon. Some brain regions were found to express only one type of receptor. For example, the cerebellum (*) expresses elevated levels of the gB receptor gene PILRA, but this was not accompanied by elevated levels of gD receptor gene expression.
Overall, the patterns were highly similar, with selective Hpc expression in both male and female, and close inspection revealed no major differences, although potential differential receptor expression was noted in two regions: the choroid plexus, where high-level expression was present in male but not female, and the lateral hypothalamic area (anterior region), where expression was elevated in female but not in male (data not presented). However, because the ABA microarray profiles are based on a single female individual, no firm conclusions may be drawn. To obtain an estimate of the actual level of overexpression of these receptors in Hpc, the ABA gene expression database was interrogated in differential mode in which Hpc was compared against a control brain region, the cerebellum. As shown in Table  2 , the positive control NR3C2 is overexpressed by a factor of 3.
25, whereas the housekeeping control showed no overexpression (1. 04). The three key HSV-1 receptor genes,   2 ). We also consulted the ABA to compare human versus mouse brain profiles of HSV receptor expression. Although the small size of the mouse brain does not lend itself to accurate interrogation of gene expression patterns in specific substructures (e. g. , brainstem nuclei), this analysis confirmed enriched expression of Myh9 (gB) and Pvrl1 (gD) in Hpc, in accordance with previous data for Pvrl1 (BIntroduction^s ection). Mouse data for Tnfrs14 were not reliable, and for Pilra, no overexpression in cerebellum was present (data not presented), in contrast to the situation for human. Overall, we conclude that enriched expression of HSV receptors in adult Hpc is a feature of both mouse and human.
Developmental profile of HSV-1 receptor expression There are marked changes in mouse brain expression profiles between gestational and postnatal/adult periods (BIntroduction^section). To address the developmental profile of human HSV-1 receptors, we consulted Human Brain Transcriptome (HBT) database  (Johnson et al. 2009; Kang et al. 2011). This also provided independent verification of results generated by ABA. HBT data are for a range of ages, but for a restricted number of brain regions, and to simplify analysis, we focused on five developmental stages as follows: 140 days (mid-gestation), 655 days (1 year postnatal), 2000 days (4. 7 years, child), 10,000 days (26. 6 years, adult), and 30,000 days (81. 4 years, elderly). We also focused on three specific brain regions: Hpc (in which enrichment of HSV receptors in adult brain was indicated, see earlier); neocortex (NCX, another telencephalon region, cf.
2008). Mean fold overexpression levels (Hpc versus cerebellum) across all ages were 2. 90, 1. 74, and 1. 45 for MAG, MYH9, and PVRL1, respectively (values for adult only are given in Table  2 ); fold overexpression for NR3C2 (all ages) was 2. 72, whereas the housekeeping control showed no enrichment (1. 02-fold). For PILRA, in confirmation of Fig. 1  data, adult cerebellar expression levels were significantly higher than in Hpc, but this was only seen later in development, and in mid-gestation levels were uniformly low. A major discrepancy between ABA and HBT emerged, with high levels of MAG expression being seen in postnatal Hpc in the HBT database, whereas these regions were not enriched over mean brain levels in ABA. Although less authoritative than either ABA or HBT, Caracausi and coworkers report no enrichment of MAG expression in human Hpc  (Caracausi et al.
For MYH9, PVRL1, and TNFRSF144, the level of upregulation in Hpc was comparable to that observed for the mineralocorticoid receptor, the archetypical Hpc-specific transcript in mouse (discussed below). MAG (gB) expression may also be enriched in Hpc, but there was major discrepancy between the two databases we consulted (ABA and HBT), with high levels of MAG expression being seen in postnatal Hpc in the HBT database, whereas this region was not apparently enriched over mean brain levels in ABA. We have no explanation for this result, but possible explanations include the use of different hybridization probes that might detect alternative transcript splicing and/or differential background hybridization, noting that ABA is in general based on two or more probes per gene, whereas HBT relies on single probes.
Although the different human brains sampled in ABA gave slightly different expression patterns for the same hybridization target, in this study the overall profile was largely conserved (Fig. 1 ); technical issues with tissue preparation combined with genetic and environmental effects may underlie this variability. In addition, patterns were substantially conserved between male and female brain, with selective HSV receptor expression in Hpc in both male and female. There were potentially some minor differences (BResults^section); however, the ABA microarray database is based on a single female individual, and studies on a greater diversity of individuals will be necessary to address possible male/female differences in HSV receptor expression. Both databases confirm that PILRA (gB receptor) is promin cerebellum; there was no parallel enrichment of gD receptors: lack of gD receptors could explain the observation, in mouse, that inoculation of HSV into cerebellum did not give rise to severe disease  (McFarland and Hotchin 1987).
RelativeABA Allan Brain Atlas, HBT Human Brain Transcriptome database, na not applicable, nd no data, ns not significant, ne not enriched in hippocampus a Fold change overexpression scores were determined by comparing levels of gene expression in Hpc versus a control brain region (cerebellum, Cb); P values and fold change scores were computed online at ABA b Fold change overexpression scores are for adult Hpc versus cerebellar cortex and are means of values for agepoints 10,000 days (adult) and 30,000 days only (elderly adult); P values for Hpc versus cerebellar cortex, Student t test c.
Cloned DNA and plasmid transfection The human full-length ADAM8 (hADAM8) cDNA (MGC:134985; Genbank:BC115404. 1) and the remnant form ADAM8 cDNA were kindly provided by Joerg Bartsch as described previously  [27]. The enzymatically inactive mutant of hADAM8 was prepared as described previously  [28]. For transient transfection of shA8-20 cells, cultures were incubated for 48 h in the presence of 4 or 8 μg total DNA in six-well or P60 plates, respectively, with Lipofectamine 2000 (Invitrogen) transfection reagent. For transfection of HEK-293 cells, 1 or 2 μg of total DNA in Lipofectoamine 2000 was used, as indicated. Empty pcDNA3 vector (EV) or pcDNA3. 1 myc-his vector (EV-3. 1) DNA were used as negative controls.
The cards were then centrifuged to distribute the cDNA samples in the reaction wells using a refrigerated Sorvall and Heraeus bucket centrifuge at 1200 rpm (331 × g) for two 1-min runs. The plate was then sealed and the real-time PCR was carried out on an Applied Biosystems 7900HT Real-Time PCR system. The data were analyzed using SDS software. Relative miRNA expression was calculated by comparing MDA-MB-231 cells with ADAM8 knockdown to cells with the control siRNA. This experiment was performed in duplicate and miRNAs that showed greater than twofold change in both replicates were selected for study.
ELISA and RNA analysis of serum from TNBC patients All clinical investigation was conducted in accordance with the principles outlined in the Declaration of Helsinki. Serum samples used in this work were provided by the Institut Régional du Cancer Nantes-Atlantique tumor bank, funded by the Institut National du Cancer (INCa) and approved by the French Minister of higher education and research (n°. AC-2008-141). Informed consent was obtained from patients to use their surgical specimens, serum, and clinicopathological data for research purposes, as required by the French Committee for the Protection of Human Subjects (CCPPRB). Ouest IV -Nantes CCPPRB approved use of serum samples for this study (6 May 2013: n°. 357/2013). This study did not need additional ethical approval. Blood samples were collected in BD Vacutainer redtop tubes (BD Biosciences, 367837) from 37 consenting women diagnosed with TNBC in the Nantes Cancer Center (ICO, France).