dataesr/scientific-paragraphs-categorization huggingface dataset:
Regional approach The spatial distribution of the series highlights heterogeneity (Fig. 1a ). Among the 56 series of the Arctic 2k database, 40 (71 %) are from the North Atlantic sector, including Scandinavia, Iceland, Greenland and the Canadian Arctic, while 9 (16 %) represent Alaska and 5 (9 %) Siberia. This high spatial discrepancy raises the question of the influence of the over-weighting of the North Atlantic sector on the global Arctic signal. Therefore, to avoid a regional bias, we divide the Arctic area into three sectors (Fig. 2a ). The Arc_9 record located in the central part of the Canadian Arctic, between the North Atlantic and Alaska, was finally included in the North Atlantic regional mean record due to the correlation between ring width and Canadian-North American temperatures highlighted by the authors  (D'Arrigo et al.
8a ). These results suggest the occurrence of multidecadal variability superimposed on the increasing anthropogenic trend during the last centuries and which can be linked with a natural internal climate variability mode. To determine the origin of the multidecadal variability in each region, we compared the three regional mean records with two instrumental climate indices: the AMO  (Enfield et al. , 2001)  and the PDO  (Mantua et al. , 1997) , using the wavelet coherence (Figs. 9 and 10, Appendix A). Because one of the main objectives of the paper is to determine the ability of the Arctic 2k database series to mimic the climate variability recorded in the observation data, we did not use the noninstrumental AMO and PDO records to go farther back in time. The analyses were thus performed on the time intervals used to define the AMO and PDO indices, which are AD  1856 -2000 and AD 1900 -2000, respectively.
Conclusion With the publication of the PAGES Arctic 2k database, which contains proxy time series that respond to several quality criteria, it was possible to describe the climate in the Arcticsubarctic region over the last 2000 years from low-to highfrequency variabilities. Long-term tendency, secular variability and multidecadal fluctuations with a focus on the last 200 years were described using statistical and signal analysis methods. We presented three new regional mean records for the North Atlantic, Alaskan and Siberian regions. Owing to the uncertainties concerning the relationship between several proxy measurements and instrumental temperatures, climate variability has been studied based on proxy time series rather than temperature reconstructions. A large number of proxy time series in the PAGES Arctic 2k database are from the North Atlantic region, but the Siberian region, and to a lesser extent the Alaskan region, are underrepresented.
Therefore, the global Arctic-subarctic record is probably biased toward the North Atlantic climate variability. This study clearly underlines the necessity to increase the number of series, especially in Alaska and Siberia. Increasing the number of series in the Pacific Arctic, western North America and Siberia would be relevant to gain a better understanding of the global Arctic-subarctic climate variability over the last 2 millennia. Despite the spatial heterogeneity of the database, we found regional long-term tendencies similar to the millennial cooling trend recorded on the global Arctic-subarctic spatial scale, except in the Siberian region. Nevertheless, the three regions are characterized by a recent warming starting at the beginning of the 19th century. However, it is important to notice that because regional records correspond to a mix of climate variables and seasonal sensitivities, they cannot be considered as annual mean temperature reconstructions.
Acknowledgements. This is a contribution to the  PAGES 2k Network  (through the  Arctic 2k working group ). Past Global Changes (PAGES)  is supported by the  US and Swiss National Science Foundations. Marie Nicolle  was supported by the  French Ministry. Maxime Debret ,  Marie Nicolle ,  Nicolas Massei  and Anne deVernal are financed by the  France Canada research fund and Maxime Debret ,  Marie Nicolle  and  Christophe Colin  received funding from the  HAMOC  project (grant  ANR-13-BS06-0003 ). We also thank the FED CNRS 3730: SCALE. We acknowledge all the reviewers for their constructive suggestions and comments. Edited by:  Marie-France  Loutre Reviewed by: four anonymous referees.
Data availability. All the series used to produce the regional time series are from the PAGES Arctic 2k database. Citations and URLs for the original data used in this study are listed in Table  S1. The PAGES Arctic 2k database used is this study (v1. 1. 1) is archived at the National Oceanic and Atmospheric Administration's World Data Center for Paleoclimatology (WDC-Paleo) and available at https://www. ncdc. noaa. gov/paleo/study/16973. The database is also archived on figshare and available at https: //figshare. com/articles/Arctic_2k_v1_1/1054736/5. The three regional time series calculated and used in the paper are available at https://doi. org/10. 6084/m9. figshare. 5616310.
They are collectively referred to as intrinsically disordered proteins (IDPs) and it is now widely recognized that IDPs play diverse biological roles  [19]. For instance, most transcription factors  [20]  and proteins involved in cell signaling  [21]  in eukaryotes are predicted to be disordered or to contain long disordered segments. More than three-quarters of human cancer associated proteins have been classified as IDPs. In comparison, only about half of all eukaryotic proteins in the UNIPROT database are IDPs  [21]. This observation underlines the importance of intrinsic disorder in the function of proteins regulating diverse processes that are often altered in cancer. Due to the intrinsic high flexibility of IDPs, nuclear magnetic resonance (NMR) is the method of choice to study their conformational preferences  [22].
0 (data not shown). The value of 5. 7 was considered appropriate as only the two histidine residues of KISS1 will be affected (becoming predominantly protonated in the NMR sample). 1 H N , 15 N, 13 C 0 , 13 C α , 13 C β and 1 H α assignments were obtained from the analysis of two dimensional 1 H, 15 N-HSQC, 1 H, 13 C-HSQC and three dimensional HNCO, HN(CA)CO, HNCACB, HN (CO)CACB, HNCA, HN(CO)CA, HN(CA)HA, and HN(COCA)HA experiments. A partial automatic assignment of the backbone and 13 C β resonances was obtained with the program MARS  [30]  and then completed manually. Several 1 H α assignments were obtained or confirmed in the 1 H, 13 C HSQC spectrum. The assignment has been deposited in the BioMagRes-Bank (accession number 26935). Secondary chemical shift values were calculated as the difference between the measured chemical shifts and their amino-acid specific random-coil values  [31]  using nearest-neighbor amino acid sequence corrections  [32].
SAXS analysis We furthermore collected SAXS data in order to probe the overall properties of KISS1 in solution  [52]. Yet, the SAXS curve shown in Fig 5A presents no distinct features, and the Kratky representation is typical for a disordered protein, with a monotonic increase of I(s)s 2 with the momentum transfer s. We observed a concentration effect on the SAXS data at the highest concentration used, and we merged curves measured at 1 and 4 mg/mL to reduce interparticle interactions while preserving a good signal to noise ratio. We used the Scåtter program  [53]  to calculate the molecular weight of the particles with a result of 9 kDa, indicating that the SAXS data correspond with a monomeric protein. An analysis of the smallest angle data by Guinier's approach for a momentum transfer range sÁR g < 1.
3 (where R g is the radius of gyration) indicates that KISS1 has an average radius of gyration of 34. 7 ± 0. 5 Å. This value is slightly larger than expected for an IDP of 120 residues (R g RC = 30. 1 Å) suggesting that KISS1 could transiently adopt more extended structures  [54]. In order to glean information on the conformational space sampled by KISS1 in solution from our SAXS data we modeled an atomistic ensemble of 10,000 KISS1 conformers using Flexible-Meccano  [39] , where torsion angle pairs were selected randomly from a database of amino acid specific conformations in loop regions of high-resolution X-ray structures  [40]. After adding side-chains, the theoretical SAXS profile for each generated conformation was computed and then averaged over the entire ensemble. The resulting curve (Fig 5B ), which represents a canonical random coil, agrees well with the experimental SAXS curve for KISS1 (χ i 2 = 0.
Acknowledgments This work was supported by the  Ministerio de Economı ´a y Competitividad  grant  CTQ2014-56966-R  to FJB and the  SPIN-HD-ANR Chaires  d'Excellence from the  Agence National de Recherche , the  ATIP-Avenir , and the  French Infrastructure for Integrated Structural Biology  ( FRISBI-ANR-10-INSB-05-01 ) to PB. Assistance at the BM29 EMBL beamline is acknowledged.
Support was provided by:  Ministerio de Economı ´a y Competitividad  [http://www. mineco. gob. es/portal/site/mineco/]CTQ2014-56966-R to FJB;  Agence National de Recherche  [http://www. agence-nationale-recherche. fr/] SPIN-HD -ANR Chaires  d'Excellence to PB; ATIP-Avenir [http://www. aviesan. fr/en/aviesan/home/atipavenir-program]to PB; The  French Infrastructure for Integrated Structural Biology  ( FRISBI -ANR-10-INSB-05-01 ) to PB.
Collaborative Group Studies The National Cancer Institute (NCI) Cohort Consortium was formed to address the need for large-scale collaborations to pool data in cohort studies of cancer and hence to quicken the pace of research (http://epi. grants. cancer. gov/Consortia/cohort. html). The Collaborative Group was initiated within the Cohort Consortium in 2013 by investigators at The Institute of Cancer Research (ICR) in London and the National Institute of Environmental Health Sciences (NIEHS). The ICR and the NIEHS serve as the Data Coordinating Centers.
Participating cohorts This report describes the 20 cohort studies (counting the European Prospective Investigation into Cancer and Nutrition, which has many cohorts within it, as a single cohort)  (6, (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28)  with data submitted to the Collaborative Group as of June 2016. Participating cohorts are shown in Table  1  and span North America, Europe, Asia, and Australia. The numbers of female participants from these cohorts aged <55 at enrollment ranges from 5,671 (Campaign against Cancer and Heart Disease) to 117,733 (Nurses' Health Study cohort). The cohorts were initiated as early as 1950 (the Radiation Effects Research Foundation Life Span Study) or as recently as 2003 (Generations and Sister Study cohorts).
All cohorts have conducted more than one round of data collection; however, follow-up data are not yet fully available Data harmonization procedures are standardized across Coordinating Centers. Quality control checks are run on each dataset to identify (i) potential data inconsistencies for each questionnaire round (e. g. nulliparous women reporting more than zero births), (ii) inconsistencies between questionnaire rounds (e. g. number of births at follow-up being lower than at baseline questionnaire), and (iii) implausible values. Data checking procedures are automated with a shared program that was run at each Coordinating Center with standardized output. Each cohort is contacted regarding any issues that were identified, and clarifications or updates are incorporated into the study-specific dataset.
If homogeneity assumptions are not violated, we pool data into a single dataset to conduct aggregate analyses stratified by study and adjusted for potential confounders that are available in all included studies. In both approaches, Cox regression models are used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer  (42). Regression models are constructed with age as the time scale such that person-time is accrued from age at cohort entry until breast cancer diagnosis, age at last follow-up, or other exit age, whichever occurred first. Follow-up time is stratified by time-updated exposures obtained from follow-up questionnaires, as appropriate. We test the proportional hazards assumption for exposures of interest, and in case of time-varying associations, e. g.
The association between adiposity and premenopausal breast cancer has been reported to vary by ethnicity, with strong associations in Caucasian, but not in Asian  (84)  or African-American (85), women, and associations are possibly stronger for ER+ than ER-premenopausal breast cancer  (73). It is not clear what level of BMI confers the highest breast cancer risks -one study reported a non-linear association between BMI and risk, with the highest risk around 24 kg/m 2 (72). The Collaborative Group, with its large number of cases in the pooled dataset and data on a wide range of risk factors, will be able to clarify the contribution of premenopausal adiposity to breast cancer risk, by examining which subtypes of breast cancer are affected, analyzing associations by exposures such as menstrual factors, and by assessing the effect of changes in adiposity over time.
Opportunities and challenges The Collaborative Group is an international collaboration formed to address etiological factors for breast cancer that may be particular to, or differ in, premenopausal or perimenopausal women. By harmonizing a wide range of exposure variables across 20 studies and developing quality assurance and analysis programs, our collaboration is in a position to conduct initial analyses of pregnancy, obesity and physical activity, and to leverage the research infrastructure and established collaboration model for investigations of other risk factors. Our initial aims do not require the use of biospecimens. However, biospecimens have been collected in many of the participating studies, as described in the Cancer Epidemiology Descriptive Cohort Database (available at https://cedcd.
Although the existence of national identifiers makes it theoretically possible to identify women who may contribute information to more than one study in a country, the logistics for obtaining approval and merging datasets can be prohibitive. Therefore, we have worked with study investigators to identify the individual cohorts within a country with the most relevant information for specific Collaborative Group aims, and to develop strategies for excluding specific geographic regions from one cohort, but not another, where overlap of cohort catchment areas is known to exist. The value of cancer consortia to address scientific questions efficiently and create new opportunities has become increasingly recognized  (104). Conducting analyses across multiple studies requires ongoing communication and transparency.
Our Collaborative Group holds in-person working group meetings in conjunction with the NCI Cohort Consortium annual meeting, as well as regular telephone conferences. These meetings provide a forum to discuss additional hypotheses that can be addressed in the future to maximize the value of the created infrastructure. The Cohort Consortium provides valuable coordinating and communication services and dedicated time and space through the annual meeting; however, other research support for data preparation, ongoing infrastructure development, and dedicated time for collaboration remains a challenge faced across many large-scale projects. Our Collaborative Group and others continue to work to identify and streamline data sharing models to maximize productivity and collaborative opportunity.
Acknowledgments We wish to acknowledge all study participants, staff, and participating cancer registries as well as  Hoda Anton-Culver ,  Jianwen Cai ,  Jessica Clague ,  Christina Clarke ,  Dennis Deapen ,  Niclas Håkansson ,  Allison Iwan ,  Diane Kampa ,  James Lacey ,  Eunjung Lee ,  Siew-Hong Low ,  David Nelson ,  Susan Neuhausen ,  Katie O'Brien ,  Hannah Park ,  Jerry Reid ,  Peggy Reynolds ,  Sophia Wang ,  Renwei Wang ,  Mark Weaver ,  Jiawei Xu ,  Jeffrey Yu , and  Argyrios Ziogas. Financial support: Support for this research comes, in part, from the  Avon Foundation  ( 02-2014-080 );  Breast Cancer Now ;  The Institute of Cancer Research, London ; the  United States National Institutes of Health National Institute of Environmental Health Sciences  ( Z01 ES044005 ;  P30 ES000260 ) and  National Cancer Institute  ( UM1 CA176726 ;  UM1 CA186107 ;  UM1 CA182876 ;  UM1 CA182934 ;  UM1 CA164974 ;  R01 CA058420 ;  R01 CA092447 ;  CA077398 ;  CA144034 ); the  United States National Center for Advancing Translational Sciences  ( KL2-TR001109 ), the  National Program of Cancer Registries of the Centers for Disease Control and Prevention , and the  Department of Energy ; the  Swedish Research Council  and  Swedish Cancer Foundation ; the  Japanese Ministry of Health, Labour and Welfare ; the  Hellenic Health Foundation ; Karolinska Institutet Distinguished Professor Award Dnr:  2368/10-221 ;  Cancer Council Victoria  and the  Australia National Health and Medical Research Council  ( 209057 ;  396414; 504711 ); the  State of Maryland , the  Maryland Cigarette Restitution Fund , and the  United Kingdom National Health Service  funding to the  Royal Marsden/ICR NIHR Biomedical Research Centre.
Twice-daily magnesium oxide supplementation has been tested in PXE patients in a 2-year clinical trial (ClinicalTrials. gov NCT01525875). However, the results had not been published at the time of writing. It has also been suggested that a high calcium intake in early life correlates with severity of PXE, although it is not known whether a low-calcium diet in infancy would be feasible with a view to restricting ectopic mineralization. In experiments with Abcc6 -/- and Enpp1 asj mice, the administration of high oral doses or lower subcutaneous doses of bisphosphonates or etidronate prevented ectopic mineralization  [143, 144]. Lastly, it has been postulated that protein conformation modifiers may allow synthesis of a functional, full-length ABCC6 protein. In in vitro experiments with polarized MDCKII cells  [145] , wild-type ABCC6 protein localized to the basolateral plasma membrane.
Materials and methods English and Chinese databases were searched from their inception to March 2016 for randomised controlled trials (RCTs) evaluating oral A. Paniculata without language barriers (Protocol ID: CRD42016035679). The primary outcomes were improvement in ARTI symptoms and adverse events (AEs). A random effects model was used to pool the mean differences and risk ratio with 95% CI reported. Methodological quality was evaluated using the Cochrane risk of bias tool; two reviewers independently screened eligibility and extracted data.
Search strategy and study selection MEDLINE, EMBASE, AMED, Cochrane Library, CINAHL, China National Knowledge Infrastructure (CNKI), Wan Fang, Sino-Med Database, and Chinese Science and Technology Journal Database (VIP) were searched from their inception to March 2016. A range of freetext words and indexed terms related to "Andrographis Paniculata" and "respiratory tract infection" were searched. The reference lists of studies meeting the inclusion criteria were searched to identify additional relevant studies. A detailed search strategy and search term alternatives for each database are available as supporting information; see S2 File. There were no exclusions made based on language. Literature searching (XYH, RHW) was followed by independently screening with at least two authors (XYH, RHW, ML).
Data extraction and management A data extraction spreadsheet was designed and piloted with appropriate changes made for this review. The form identified trial characteristics, characteristics of trial population and conditions, details of interventions in all trial arms according to the consolidated standards of reporting trials (CONSORT) herbal extension in terms of features of herbal intervention  [40] , details of concomitant interventions, quality assessment, and findings on efficacy, effectiveness and AEs. Two reviewers extracted study data independently for Chinese-language (XYH, RHW, LL) and English-language (ML, CB) trials, with findings compared and agreed.
Although the Chinese government launched a special campaign to promote the rational use of antimicrobials in healthcare settings in the 2011 healthcare reform, this has yet to be implemented in many places in China  [43]. Antibiotics are prescribed on patients' initial visit if there were suspicions of bacteria inflammation, therefore scripts immediately issued at the time of consultation was recorded. Trials that did not report either our primary and or secondary outcome measures were excluded from this review. Timing of effect measures: Some studies may have used a repeated measures approach. Timings of measures for each included trial were documented with commonly reported time points explored if there was sufficient data available. All outcome measures were assessed at baseline and data for all time points were extracted with the aim to pooling those trials that collected data at similar time points.
Dealing with missing data Where data was missing or incomplete, we contacted study authors to obtain this where possible. If the means were reported without standard deviations, we calculated the standard deviation from the information reported such as p-values, F-values or confidence intervals. As far as possible, we utilised intention to treat (ITT) analysis data for all outcomes. However, most included trials reported complete cases only; and complete case data were the primary analysis dataset. For each outcome, the number of participants whose data was available at baseline and at follow up, and the rate of loss to follow-up were recorded.
e. A. Paniculata plus usual care versus usual care)  [62] [63] [64] [65] [66] [67] [68] [69] [70]. Twenty-six included trials reported no attrition. Among the 7 trials that had dropouts, three trials reported 3-8% dropout and conducted ITT by assuming no effect for dropouts. No per protocol analysis was performed for those three trials  [56, 58, 73]. Two trials reported dropouts (1%  [78]  and 6%  [52] ) without ITT analysis. Another trial reported 25% dropout and provided both ITT and per protocol analysis findings  [76]. The author suggested that the dropout rate in two groups were equal and that the potential reason for large dropout may have been related to three weeks' winter holiday. One trial did not clarify how missing data was dealt with  [70]. One trial  [79]  published a protocol containing information on outcome measures and follow-up points that were consistent with the main trial report.
Strengths and limitations Cochrane methodology was followed with a protocol of this systematic review registered and published online. A broad search strategy including both English and Chinese databases was adopted without language restrictions. Papers identified were screened and eligible trials extracted independently by two reviewers. We attempted to include grey literature by seeking manufacturers' reports and attempted to contact original authors for missing data. A number of studies including a substantial patient sample were identified; characteristics of the herb were documented following the criteria of CONSORT herbal extension. Methodological quality of included trials was restricted as randomisation was not well documented; 73% of the trials included were not blinded; where ITT analysis were performed, loss to follow-up data were counted as no effect  [56, 58, 73] ; and most trials were published without a protocol available.