dataesr/scientific-paragraphs-categorization huggingface dataset:
Within the whole dataset, 72 subjects (44 PersA, 28 ClinR and 10 of ClinR subjects are ComR) had whole blood methylation data and 97 (44 PersA, 53 ClinR and 19 of ClinR subjects are ComR) had nasal methylation data, with 66 subjects providing both (Fig. 1 ). White blood cell composition was estimated, and we did not observe significant cell composition differences among PersA, ClinR and ComR group in six cell types. (Additional file 3: Figure  S2 ).
Discovery cohort Lifelines EGEA  no obvious inflation of the results. We verified the CpG sites identified from whole blood samples in nasal brushes, and found that one CpG (cg15404785) associated with ClinR showed nominal significance (P < 0. 05) and the same direction of effect in nasal brushes (Table  S7 ). Four ClinR-associated CpG sites were correlated to expression level of four genes in cis (nominal significant P < 0. 05) in nasal brushes, with one pair (cg07673230-RPL30 (Ribosomal Protein L30)) also being nominal significant and in the same direction in the PIAMA dataset (Additional file 2: Table  S8 ).
318. Eight of the ComR-associated CpG sites identified from whole blood also showed nominal significance in nasal brushes with the same direction of effect (Additional file 2: Table  S13 ). Seven ComRassociated CpG sites were correlated to expression level of nine genes in cis (nominal significant P < 0. 05) in nasal brushes, and four pairs also showed nominal significant and in the same direction in PIAMA dataset (Additional file 2: Table  S8 ).
12 × 10 -7 ). To evaluate potential SNP effects within the probe for the two replicated CpG sites, the β value distributions were visually assessed in the discovery cohorts (Additional file 3: Figure  S6 ), and no bimodal distribution was detected indicating no underlying SNP effect within the probe. The regional co-methylation plots of genes annotated to replicated CpG sites are shown in the Additional file 3: Figure  S7 , which showed that cg13378519 is located in the promoter region of PEX11B gene, and cg24788483 is located in heterochromatin region of TCF7L2 gene. We did not identify any SNP that was associated with the two CpG sites using an online database  [19]. We verified if the results of the two replicated CpG sites were affected by inhaled corticosteroids (ICS), known to affect DNA methylation at multiple sites in the genome (Additional file 3: Figure  S8 ).
Discussion In this study, we identified one CpG site associated with ClinR and a different CpG site associated with ComR from whole blood, that were replicated in independent cohorts. We also revealed that 25 CpG sites were associated with asthma remission phenotypes in nasal brushes. In the nasal dataset, two differentially methylated regions were previously observed in another DNA methylation study of asthma remission using bronchial biopsies. This is the first epigenome-wide association study of asthma remission in both whole blood and nasal epithelial cells. This study is important since understanding asthma remission may provide new leads for future asthma treatments, and epigenetic studies may help to reveal these cellular mechanisms. The two replicated CpG sites were annotated to genes which were not known to be involved in asthma (remission) before.
SCGs and ipsilateral TG were collected 33-35 days later. e ddPCR quantification of HSV genomes in TG and SCG from latently infected mice either left untreated (Controls, CTRL circles, n = 12) or administered m5 + m8 (squares, n = 12). p = 0. 006 and p = 0. 01 for SCG and TG, respectively. f NGS analysis of SCG and TG from treated mice to detect mutations at either the m5 (closed circles) or m8 (open circles) target sites. ns: not significantly different from controls, *p < 0. 05, **p < 0. 01, ***p < 0. 001, significantly different from controls. All data are presented as mean values ± SD. Statistical analysis was conducted using unpaired multiple t-test without correction for multiple comparison. Source data are provided as a Source data file. (Fig. 1a-d ). Quantification by ddPCR showed similar levels of HSV in the TG of all treated animals (Supplementary Fig.
We obtained high quality single-cell expression data from 2319 purified TG neurons and 2041 SCG neurons (99,817 mean reads and 5,908 median genes per cell for TG; 94,797 mean reads and 5635 median genes per cell for SCG). To determine whether specific subtypes of neurons were infected by HSV and targeted by each AAV serotype, we first classified neurons into groups based on gene expression profiles. Principal component analysis (PCA) of the single-cell gene expression data identified transcriptionally distinct clusters of neurons for each tissue: 5 for the SCG and 10 for the TG. As expected, SCG (autonomic) and TG (sensory) neurons fully segregated from one another (Fig. 7a  and Supplementary Fig. 6a ). The cell clusters in the TG correlated well with clusters identified previously in the DRG  28, 29  and the TG  30.
n/a: not applicable. f-i Gene editing at the m5 target (f, g) site and m8 target site (h, i) were quantified by T7E1 assay in SCG (f-h) or TG (g-i). ns: not significantly different from controls, *p < 0. 05, **p < 0. 01, *** p < 0. 001, **** p < 0. 001 significantly different from controls. All data are presented as mean values ± SD. Statistical analysis was conducted using one-tail, unpaired t-test. Exact p values are indicated in Table  2. Source data are provided as a Source data file. delivery by single-stranded (ss)AAV vectors, while meganucleases fit easily into the more transcriptionally efficient selfcomplementary (sc)AAVs, which do not require de novo second strand synthesis or intermolecular annealing for transgene expression. It has been demonstrated previously that the use of scAAV vectors rather than ssAAV greatly enhances transduction efficiency  37.
T7 endonuclease 1 (T7E1) assay. The T7 endonuclease assay and quantification to determine the levels of gene disruption were performed as follows. After PCR amplification of target site from HSV genomes, followed by purification using Zymo Research clean and concentrator-5 kit (Zymo Research, Irvine CA), 300 ng of DNA amplicon was denatured for 10 min at 95 °C and slowly reannealed by cooling down to room temperature. DNA was then digested with 5-10 units of T7 endonuclease (New England Biolabs,) for 30-60 min at 37 °C and resolved in an agarose gel. Quantification of gene disruption was performed using ImageJ software (NIH  49  ) and calculated using the formula: 100 × (1 -[1fraction cleaved]1/ 2) where fraction cleaved = density of cleaved product/(density of cleaved product + density of uncleaved product).
The SCG and TG libraries were pooled and distributed over 8 sequencing lanes. Image analysis and base calling were performed using RTA Version 1. 18. 66. 3. Sequencing reads were processed with the 10X Genomics 'Cell Ranger' v2. 1. 0 and with Seurat v2. 3. 4  50. We obtained high quality sequence data from 2372 purified TG neurons and 2,172 SCG neurons. Statistics and reproducibility. GraphPad Prism 7 software was used for statistical analyses. Comparison of HSV loads was performed with multiple t-test, with alpha = 0. 05%. Each tissue was analyzed individually, without assuming a consistent SD. HSV and AAV distributions in scRNA-seq experiments were analyzed using the χ 2 test with alpha = 0. 05. Because tissue from animals injected with the different AAV serotype/transgene were pooled, cell counts were normalized to input by multiplying cell count by number of animals receiving that serotype divided by total number of animals.
Acknowledgements This research was supported by  NIH  grants  R21AI117519  and  R01AI132599  (Jerome), the  Caladan Foundation , and the  Genomics, Experimental Histopathology and Comparative Medicine Shared Resources of the Fred Hutch/University of Washington Cancer Consortium  ( P30 CA015704 ). We thank  Lawrence Corey  and  Ashley Sherrid  for critical reading of the paper.
Data availability Single-cell RNA sequencing data is available via GEO under accession GSE151811. Raw sequence data has been uploaded to SRA under BioProject PRJNA330548. Meganuclease sequences are Cellectis proprietary information; material and information requests can be made to R. Galetto (roman. galetto@cellectis. com) and P. Duchateau (philippe. duchateau@cellectis. com). Source data are provided with this paper.
In principle, the prompt-photon production process πN → γX can constrain the gluon content of pions through the Gq → γq subprocess, but the experimental uncertainties are large. Production of heavy quarkonia, like J/ψ and Υ(1S), with the pion beam has distinctive advantages: The cross sections are large and they can be readily detected via the dimuon decay channel. These datasets have been shown to be sensitive to both the quark and gluon distributions of the incident pion with model-dependent assumptions of quarkonia fragmentation  [3, 4]. The interesting possibility of accessing the pion PDFs from leading neutron deep inelastic scattering (DIS) data has been considered with promising results  [5, 6]. However, this method is subject to large systematic uncertainties, and further studies on the uncertainties of the pion splitting function and the offshellness of virtual pion are required  [7, 8].
Since the nucleon PDFs are known with good accuracy, the measurement of the x F distribution of J/ψ production with the pion beam provides, within the theoretical model uncertainties, valuable information about the pion quark and gluon partonic distributions. Our study is performed using next-to-leading-order (NLO) CEM calculation, including the recent nucleon PDFs. The available pion-induced J/ψ data on hydrogen and several light-mass nuclear targets are compared to calculations using the available pion PDFs. Over the broad energy range considered, all pion PDF sets provide reasonable agreement with the x F -integrated cross sections. In contrast, for the x F distributions, we find that the agreement between data and calculations strongly depends on the magnitude and shape of the pion gluon distribution.
III. PION PDFS Pion-induced Drell-Yan data are included in all global analyses for the determination of the pion PDFs. However, Drell-Yan data  [56] [57] [58] [59]  constrain mainly the valence-quark distribution. Without additional observables, the sea and gluon distributions remain practically unknown. Their magnitude can be only inferred through the momentum sum rule and valence-quark sum rule. Different approaches have been taken to access the gluon and sea quark distributions: (i) utilizing J/ψ production data in OW  [11] ; (ii) utilizing the direct-photon production data  [60]  in ABFKW  [12] , SMRS  [13] , GRV  [14] , and xFitter  [17] ; (iii) utilizing leading neutron DIS  [61, 62]  in JAM  [18]. In addition, some pion PDFs are based on theoretical modeling. For example, GRS  [15]  utilized a constituent quark model to relate the gluon and antiquark density, and BS  [16]  assumed quantum statistical distributions for all parton species with an universal temperature.
The uncertainties of xFitter and JAM PDFs are not taken into account here. The results and the comparison with data are displayed in Fig. 2. The total cross sections for the four PDFs exhibit quite similar √ s dependencies, and all agree reasonably with the data. The differences between them are visible through the F factors, which vary from 0. 05 to 0. 09. As a general feature, the q q contribution dominates at low energies, whereas the GG contribution becomes increasingly important with increasing √ s. However, the relative fractions of q q and GG contributions as a function of √ s vary considerably, reflecting the differences between the corresponding parton distributions. For SMRS and GRV, the GG contribution starts to dominate the cross section beyond √ s = 13 and √ s = 11 GeV, respectively, while for xFitter and JAM the corresponding values are much higher: √ s = 19 and 21 GeV, respectively.
In order to investigate further the effect led by different pion PDFs, we compare the longitudinal x F distribution of the calculated pion-induced J/ψ production cross section with a selection of fixed-target data from Fermilab and CERN experiments. Among the datasets available for pion-induced J/ψ production  [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] , we choose the ones that have large-x F coverage for either hydrogen or light nuclear targets (lithium and beryllium) in order to minimize the effects of the nuclear environment. The selected eight datasets are listed in Table  II. The beam momenta of the datasets cover the range of 39. 5-515 GeV/c, corresponding to √ s values ranging from 8. 6 to 31. 1 GeV. Some of the data listed in Table  II  involve nuclear targets. The target PDFs parametrizations are CT14nlo for the hydrogen target and EPPS16  [78]  for the lithium and beryllium targets.
Contrary to the integrated cross sections, we now allow energy dependence for the hadronization factor F which is to be fine-tuned for each dataset individually. Within the CEM and heavy-quark pair production framework introduced in Sec. II, we per-   II  are not included in the error estimation, since they are correlated systematic errors and will not affect the χ 2 but only contribute to the uncertainty of F factor. To compare the four pion PDFs on an equal footing, the uncertainties of the more recent PDFs are not included in the calculation of χ 2. We will discuss the impact of PDF uncertainties on the fit results later. formed The χ 2 /ndf value of the best fit is also displayed in the plot. The estimated individual q q and X ψ J/ → N - π FIG. 2. The product of J/ψ dimuon decay branching ratio (Br) and J/ψ production cross sections at x F > 0 for the π -N reaction, calculated with four pion PDFs (SMRS, GRV, xFitter and JAM) is compared with data (solid circles)  [46, 67].
The black, blue, and red curves represent the calculated total cross section and the q q and GG contributions, respectively. The shaded bands on the xFitter and JAM calculations come from the uncertainties of the corresponding PDF sets. The SMRS and GRV PDFs contain no information on uncertainties. GG contributions are denoted as blue and red lines, respectively. There is a negligible additional contribution from the qG subprocess, shown as green lines, to the total cross sections in the NLO calculation. The calculated value of the qG contribution is negative  [53]. The uncertainties of xFitter and JAM PDF sets are displayed as shaded bands. In the following subsections (Secs. IV A- TABLE II. The J/ψ production datasets with π -beam used in the analysis, listed in order of decreasing beam momentum.
B. Fermilab E705 experiment The Fermilab E705 experiment  [69]  used a 300 GeV/c negative hadron beam (with 98% pions) scattered off a 33-cm-long lithium target. Data were also collected with a positive hadron beam consisting of protons and positive pions. Thanks to the open geometry spectrometer, an excellent mass resolution was achieved, allowing a measurement of the J/ψ peak in the mass range between 2. 98 and 3. 18 GeV/c 2. Since the final number of J/ψ events was not explicitly given, we estimate it from the published statistical errors to about 6000 events for the negative pion beam. The final cross sections have a normalization uncertainty of 11. 1% and cover the range -0. 1 ≤ x F ≤ 0. 45 in bins of 0. 05. The comparison of our calculations with the experimental cross sections is shown in Fig.
The total cross sections and q q and GG contributions are denoted as black, blue, and red lines, respectively. components were identified using Cherenkov counters. Moreover, in addition to a heavy platinum target, a liquid hydrogen target was also used, thus eliminating all possible nuclear effects. For all three energies, the cross sections have a normalization uncertainty of 13%. In the present study we consider only the NA3 hydrogen data. Unfortunately, these invaluable numerical cross sections were never published and could be retrieved only from the figures in the published paper  [70]  and unpublished thesis  [79]. For the 280 GeV/c data taking, the authors used a 50-cm-long hydrogen target, resulting in 23350 J/ψ π -events in the dimuon mass region between 2. 7 and 3. 5 GeV/c 2. The retrieved data are available in 17 x F bins of 0.
D. CERN NA3 experiment, 200 GeV/c The data at 200 GeV/c incident momentum were taken with a 30-cm-long hydrogen target. With the negative hadron beam 3157 pion-induced J/ψ events were collected. The retrieved data extend from x F = 0. 05 to x F = 0. 85. The comparison of the NLO calculation with the data is shown in Fig. 6. The agreement with the data is fair for all PDF sets, although the general trend persists: The most recent xFitter and JAM global fits have slightly worse χ 2 /ndf values. We also note that, as the incident momentum decreases, the importance of the q q term increases, particularly for the larger values of x F. The GG contribution dominates the cross section for the calculation with the GRV PDFs up to x F = 0. 6. In contrast, for the JAM PDFs, the corresponding value is much lower: x F = 0.
butions were added to the prompt cross section values shown, using the described procedure in reverse order. The comparison of the NLO CEM calculations with the WA11 data is shown in Fig. 7. The resulting χ 2 /ndf values are larger than for the NA3 data, pointing to additional systematic errors either in the original data or in the procedure of retrieving them. Not surprisingly, however, the The total cross sections and q q and GG contributions are denoted as black, blue, and red lines, respectively. overall conclusions are similar to the ones made previously for the 200 GeV/c data. The calculations with SMRS and GRV are in better agreement with the data than xFitter and JAM. The total cross sections and q q and GG contributions are denoted as black, blue, and red lines, respectively.
F. CERN NA3 experiment, 150 GeV/c The NA3 data at 150 GeV/c were taken with a 30-cm-long hydrogen target. The statistics is large, as 16952 events were reported. The original data cover the x F region between 0. 025 and 0. 975, in bins of 0. 05. The data retrieved from the published figures extend to x F = 0. 925. The comparison with the NLO CEM calculation is shown in Fig. 8. The calculated χ 2 /ndf values are rather small, pointing to somewhat overestimated experimental error bars. Nevertheless, they remain larger for the two most recent PDF sets. The overall trend previously observed is confirmed. The total cross sections and q q and GG contributions are denoted as black, blue, and red lines, respectively. 0. 5 - 0 0. 5 1 F x 3 -.
I. Observations As a general observation, both LO and NLO CEM calculations provide a reasonable description of x F distributions of J/ψ production in the energy range considered (Figs. [3] [4] [5] [6] [7] [8] [9] [10]. We note that the large difference in the magnitude between LO and NLO is compensated by the F factor. The F factors for the xFitter and JAM PDFs are relatively stable across the range of collision energies, The total cross sections and q q and GG contributions are denoted as black, blue, and red lines, respectively. 0. 5 - 0 0. 5 1 F x 3 - while the factors for SMRS and GRV PDFs show a mild rise toward low energies. From the comparison between data and calculations, interesting observations are summarized below. (i) The importance of the GG contribution relative to that of q q is greatly enhanced in the NLO calculation.
As for the description of the large-x F data points for the pion beam larger than 125 GeV/c, the χ 2 /ndf values with the NLO calculations generally improve for the results with experiment  [74]. The total cross sections and q q and GG contributions are denoted as black, blue and red lines, respectively. SMRS and GRV, whereas those with xFitter and JAM become worse, compared to the LO ones; for example, see Fig. 3. (ii) At low energies, the GG contribution is relatively small, but it increases rapidly with the increase of energy. The fraction of GG component is maximized around x F = 0, corresponding to the gluon density of pions at x ∼0. 1-0. 2. As a result of the rapid drop of the pion's gluon density toward x = 1 shown in Fig. 1 (c), the GG contribution decreases dramatically toward large x F.
V. SYSTEMATIC STUDY Through the comparison of data with calculations over a broad energy range, we have two major findings: (i) The large-x F distribution of J/ψ production is sensitive to the pion gluon density; (ii) the central values of gluon densities of the recently available JAM and xFitter fall off too rapidly at large x and fail to describe the x F distributions of J/ψ data. Judging from the consistency of observation for the datasets with proton and nuclear targets, the unaccounted nuclear medium effects such as the energy loss effect are unlikely to change the conclusions. The uncertainties provided by xFitter and JAM can have an impact on the χ 2 values of the fits. We perform a new fit where the PDF uncertainties are added as theoretical errors into the covariance matrix of measurements for the calculation of the χ 2 values.
For this dataset at the largest beam momentum of 515 GeV/c, the GG contribution is dominating in the CEM NLO calculation. A reduction of m c from 1. 5 to 1. 2 GeV/c 2 reduces the relative contribution of q q and leads to a deterioration of χ 2 /ndf for both GRV and JAM. Nevertheless, this effect is particularly significant in the case of JAM. With a reduction of the q q contribution, the large-x gluon density of JAM PDFs is not strong enough to sustain enough GG contribution in accounting for the cross sections at large x F. The information of F factor and χ 2 /ndf for the systematic study of this dataset with the SMRS, GRV, xFitter, and JAM pion PDFs, is shown in  From the systematic study of all datasets, the NLO CEM results clearly favor SMRS and GRV, especially at high energies. The χ 2 /ndf, representing the performance of data description, strongly correlates with how large the magnitude of gluon density is in the valence region.
VII. SUMMARY We have examined the available pion PDFs extracted from the global fit to Drell-Yan, promptphoton production or leading neutron DIS data. These PDFs present pronounced differences, particularly in the gluon distributions. We have calculated their total and x F differential cross sections for pion-induced J/ψ production using the CEM framework at NLO. The calculations are compared to the data using hydrogen and light nuclear targets. We observe the importance of the gluon fusion process in J/ψ production, especially at high (fixed-target) energies. We find that this dominance is even more pronounced in the NLO calculation. Since the calculated shapes of x F distributions of GG and q q contributions are directly related to the parton x distributions of corresponding PDFs, a proper description of J/ψ production data, especially for x F > 0.
5, imposes a strong constraint on the relevant pion's parton PDFs. Among the four pion PDFs examined, the CEM NLO calculations favor SMRS and GRV PDFs whose gluon densities at x > 0. 1 are higher, compared with xFitter and JAM PDFs. The GG contribution from the latter two pion PDFs drops too fast toward x F = 1 to describe the data. Within the CEM, our study clearly indicates that the fixed-target pion-induced J/ψ data could be useful in constraining the pion gluon density, particularly at the large-x region. It will be interesting to perform similar studies using the more sophisticated NRQCD approach. In the near future, new measurements of Drell-Yan as well as J/ψ data in πA reactions will be available from the CERN COMPASS experiment. While further theoretical efforts are required to reduce the model dependence in describing the J/ψ production, we believe that it is important to include the existing large amount of pion-induced J/ψ data as well as the new ones in future pion global analysis.