dataesr/scientific-paragraphs-categorization huggingface dataset:
We also only considered features with intensities that were more than three times the background value and considered these as "true peaks. " Only m/z signals with at least eight true peaks for the samples precursors (MS1) and fragments datasets were considered for PCC calculation. A precursor mass feature is further defined if its intensity across sample significantly correlate with the decreased intensity of the same mass feature subjected to low or high collision energies and that this feature is not annotated as an isotope peak by CAMERA. The correlation analysis was then conducted by calculating all possible precursor-to-product pairs within 3 s-estimated retention time window for peak deviation. m/z values were only considered as fragments if they were lower than that of the precursor and MS/MS fragmentation occurred in the same sample position within the dataset as the precursor from which it is derived.
First, a standard NDP, also referred to as cosine correlation method, was used to score fragment similarity among spectra using the following equation NDP = A second scoring method involving the analysis of shared NLs among individual MS/MS was implemented. For this, we used a list of 52 NLs commonly encountered during tandem MS fragmentation and more specific ones that had been previously annotated for MS/ MS spectra of N. attenuata secondary metabolite classes (data file S1)  (9, 26). A binary vector of 1 and 0 was created for each MS/MS corresponding to present and absent of certain NL. NL similarity score was calculated for each pair of binary NL vectors based on Euclidean distance similarity. ( ∑ i S1&S2 W S1,i W S2,i ) 2 ───────────── ∑ i W S1,i 2 ∑ i W S2,i.
MS/MS biclustering and molecular networking To perform biclustering, we used the R package DiffCoEx, which is based on an extension of the weighted gene coexpression analysis (WGCNA). Using NDP and NL-scoring matrices for MS/MS spectra, we computed a comparative correlation matrix using DiffCoEx. The biclustering was performed with the parameters of "cutreeDynamic" set to method = "hybrid", cutHeight = 0. 9999, deepSplit = T, and minClusterSize = 10. The R source code of DiffCoEx is downloaded from additional file 1 by Tesson et al. (57) ; the required R WGCNA package can be found at https://horvath. genetics. ucla. edu/html/ CoexpressionNetwork/Rpackages/WGCNA. To perform MS/MS molecular networking analysis, we calculated pairwise spectral connectivity based on both NDP and NL similarity types and visualized the topology of the network using Cytoscape software with the organic layout in the yFiles layout algorithms extension app for Cytoscape.
Mutation screening All the DNA samples were screened for germline mutations using the On-Demand Research Assay on the Ion S5 system (both ThermoFisher Scientific, Waltham, MA, USA). Each DNA sample was checked for concentration using a Qubit 3. 0 Fluorometer (Thermo Fisher Scientific). The concentration of input DNA was then adjusted to 50 pmol. The library and template preparations were performed using the automated Ion Chef System, then sequenced in Ion S5 with Ion 520 Chip (all Thermo Fisher Scientific) according to the manufacturer's instructions. Sequencing results were aligned to the hg19 human reference genome and analyzed using the Ion Reporter Software Version 5. 10 (Thermo Fisher Scientific). The variant frequency cut-off for the detection of gene germline mutation was defined as 20%, as recommended by a previous study  [7].
RT-PCR When Human Splicing Finder (HSF) software (http:// www. umd. be/HSF3/) predicted a splicing disruption caused by a mutation, we performed a cDNA-based analysis. To this end, RNA isolated from lymphocytes was reverse transcribed into cDNA using the Transcriptor First Strand cDNA Synthesis Kit (Roche), according to the manufacturer's protocol. We then evaluated the possible impact on transcription by performing a PCR, subsequently separating the products in low melting 2% agarose gel with Red Safe ™ staining. After that, the bands were isolated and the DNA extracted using NucleoSpin ® Gel and PCR Clean-up (Macherey-Nagel, Düren, Germany) was sequenced. Oligonucleotides and PCR conditions are available on request.
Sufficient coverage was sought to ensure that all bases within ROIs were covered at a minimum of 30×. The Ion reporter pipeline parameters were adjusted to ensure greater control over the variant calling quality. In a first approach, a training set of different mutations in high penetrance genes was used to evaluate the performance of the panel. All the variants were both correctly sequenced and annotated (data not shown). A total of 18 Pathogenic or Likely Pathogenic variants (PV/LPV) were identified in 18 cancer cases (14%), affecting 9 different genes with a current clinical utility for each hereditary cancer condition (Table  2 ). These alterations represented 13 Single Nucleotide Variants (SNVs), 4 deletions and 1 insertion, all in heterozygosis, and resulted in: 7 missense variants, 5 frameshift variants, 3 nonsense variants (resulting in premature termination codon) and 3 splicing variants  ( 1 not yet reported in consulted databases).
We did not detect any aberrant transcript, either for the c. 4076 + 4T > G variant in BLM or for c. 4473C > T in ATM. In an attempt to contribute to clinical actionability, in particular to therapy selection, we consulted the OncoKB database. We were looking for a registered response to specific targeted drugs in relation to the mutation profile of the patients. It may be considered that the ATM, BRCA2 and CHEK2 pathogenic mutations could be determining a PARP inhibitor sensitivity, as already registered. Moreover, in the case of ATM pathogenic mutations, the DNA-PKc and ATR inhibitors were expected to be effective. According to this information, a total of 6 patients could benefit from targeted therapy options.
Created with BioRender. com. effects,  [123]  while IL-10 mRNA shuttled in EVs also rescued cell viability. [124] The miRNA cargo of EVs in particular exhibits prosurvival effects, as exemplified by knockout of Argonaute-2, a key miRNA effector molecule, which abrogated EV-mediated nerve repair in a rat optic nerve crush model. [125] miR-21 has been identified as an important EV component that promotes cell survival in vitro  [126]  and in a rat MI model  [127]  through activation of the PI3K/Akt pathway. miR-let7-5-p shuttled in EVs also contributes to promoting cell survival. [128] Endogenous cell migration and proliferation at the site of injury are integral steps in the tissue healing cascade. EVs promoted ischemic wound healing and the long noncoding (lnc) RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was responsible for EV-mediated increases in cell migration,  [24]  while EV-shuttled Wnt5a and Wnt5b also mediated increased migration and proliferation.
Future Challenges for the Clinical Translation of MSC Secretome Delivery To date, the clinical evaluation of MSC-CM and MSC-EVs is limited, but significant trials are required to establish the efficacy of this approach. Several clinical trials and case studies have addressed the potential of MSC-CM, and report safety and potential efficacy, including for multiple sclerosis,  [38]  skin wound healing,  [237]  hair follicle regeneration,  [238]  and psoriasis. [239] Another current trial is listed with the goal of evaluating MSC-CM for healing in chronic skin ulcers (phase 1, NCT04134676). While these clinical approaches are using bolus CM administration, one recent clinical report found that MSC-CM derived from allogenic BMSCs delivered via biomaterials successfully regenerated bone tissue in eight patients requiring bone augmentation prior to dental implant placement.
CM incorporated into atelocollagen sponges led to faster resorption and denser bone matrix compared with CM-soaked β-TCP. [36] There are also a few clinical studies using MSC-EVs targeting regeneration, although none yet delivered via a biomaterial. Allogenic MSC-EVs used to treat chronic kidney disease were reported to be safe, well tolerated, and enhanced healing. [240] A further clinical trial (phase 1, NCT03437759) using MSC-EVs was launched to determine their potential for treating refractory macular holes, with preliminary results suggesting safety and efficacy of EV administration in these cases. [241] Finally, a trial has been listed whose goal is to assess the safety and efficacy of allogenic MSC-EVs enriched with miR-124 on functional improvements in patients with acute ischemic stroke (NCT03384433).
Samples We analysed 97 serum samples from 53 patients admitted to hospitals in Paris with SARS-CoV-2 infection confirmed by  22] , and 162 serum samples from healthcare workers in hospitals in Strasbourg [23] (Table  1 ). 68 plasma samples from the Thai Red Cross, 90 serum samples from Peruvian healthy donors, and 177 serum samples from French blood donors collected before December 2019 were used as negative controls. All samples underwent a viral inactivation protocol by heating at 56 °C for 30 minutes. The potential effect of the viral inactivation protocol on the measurement of antibody levels was assessed using serum positive for anti-malaria antibodies. IgG and IgM antibody levels were measured in matched samples before and after the inactivation protocol. The viral inactivation protocol did not affect measured IgG or IgM levels (data not shown).
Serological assays In a first step, four proteins derived from SARS-CoV-2 Spike were included in the assay. This includes SARS-CoV-2 trimeric Spike ectodomain (S tri ) and its receptor-binding domain (RBD) produced as recombinant proteins in mammalian cells in the Structural Virology Unit at Institut Pasteur, while S1 (cat# REC31806) and S2 (cat# REC31807) subunits were purchased from Native Antigen, Oxford, UK. S tri and RBD were designed based on the viral genome sequence of the SARS-CoV-2 strain France/IDF0372/2020, obtained from the GISAID database (accession number EPI_ISL_406596). The synthetic genes, codon-optimized for protein expression in mammalian cells, were ordered from GenScript and cloned in pcDNA3. 1(+) vector as follows: the RBD, residues 331-519, and the entire S ectodomain (residues 1-1208).
For the purpose of evaluation of antibody kinetics, measured antibody responses from samples collected from individuals followed longitudinally after confirmed SARS-CoV-2 infection will be especially valuable. The simulations presented here predict that following SARS-CoV-2 infection, antibody responses will increase rapidly 1-2 weeks after symptom onset, with antibody responses peaking within 2-4 weeks. After this peak, antibody responses are predicted to decline according to a bi-phasic pattern, with rapid decay in the first three to six months followed by a slower rate of decay. Model predictions of the rise and peak of antibody response are informed by, and are consistent with, many sources of data  [10] [11] [12] [13] [14] 36]. Model predictions of the decay of antibody responses are strongly determined by prior information on longitudinal follow-up of individuals infected with other coronaviruses  [26] [27] [28] [29] [30] [31].
Case study of early-stage SARS-Cov-2 antibody kinetics: hospitalized patients in Hong Kong We performed a secondary analysis of data from patients admitted to Princess Margaret Hospital and Queen Mary Hospital in Hong Kong, following the primary analysis by To, Tsang et al  [1]. 23 patients with RT-qPCR confirmed SARS-CoV-2 infection were followed longitudinally for up to four weeks after initial onset of symptoms. Ten patients had severe COVID-19, all of whom required oxygen supplementation, and 13 patients had mild disease.
Acknowledgements The French COVID cohort is supported by the REACTing consortium and by the  French Directorate General for Health. Darragh Duffy ,  Jérôme Hadjadj  and  Laura Barnabei  are thanked for their work on the  Hôpital Cochin study. Arnaud Fontanet  is thanked for critical reading of the manuscript. Dionicia Gamboa  is thanked for sharing negative control samples from  Peru. Jetsumon Sattabongkot  is thanked for sharing negative control samples from  Thailand. Marie-Noelle Ungeheuer  and  Blanca Liliana Perlaza  are thanked for processing samples at the  ICAReB platform in Institut Pasteur. Shane Mansfield  and  Richard Davison  are thanked for their help in the solution of differential equations. We thank all patients and health care workers who kindly agreed for samples to be used for medical research purposes.
In the secondary analyses, data from 17,719 PD patients and 7,588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. Results: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the onlineonly cohort. Conclusions: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management.
However, these studies were generally small in sample size and predominantly performed in a cross-sectional setting. In this study, we analyzed longitudinal data from 12 PD cohorts, representing 5,946 participants, with a median of 3. 1 years of follow-up. This study had two objectives: (1) to identify the baseline differences between men and women, in terms of disease presentation, and (2) to identify the influences of sex on longitudinal symptom trajectory. Further, we analyzed the Fox Insight dataset, an online-only, PD research cohort, to assess whether the observations made using the longitudinal datasets were consistent in an independent dataset. Moreover, by analyzing the data from both PD participants and non-PD participants in the Fox Insight dataset, we were able to evaluate differences in the prevalence of self-reported outcomes between participants with and without PD.
This analysis further illustrated that some of the identified differences may be influenced by general differences between males and females, whereas others are diseasespecific. characteristics, symptoms, medical history, and PD medication data were collected. Although Fox Insight is a longitudinal study, we analyzed the data cross-sectionally for the present study because the follow-up periods were relatively short (e. g. , the median follow-up period was 0. 4 years for Non-Motor Symptoms Questionnaire). During the analysis step, we adjusted for age and disease duration. To limit the impacts of the extreme data points, we included participants from the middle 80% of the age distribution and the disease duration distribution (only among PD participants), which excluded any participants younger than the lower 10th percentile (< 46.
Measurements Clinical Data Harmonization Among the 12 cohorts Twenty-three measurements, 11 binomial and nine continuous measurements, were analyzed as outcome measures. Binomial outcomes included constipation, mild cognitive impairment, depression, daytime sleepiness, hyposmia, insomnia, wearing off, dyskinesias, RBD, restless-leg syndrome, and modified Schwab and England Activities of Daily Living Scale scores of 70 or lower (SEADL70). Some binomial outcomes had study-specific outcomes, and these criteria are summarized in the Supplemental Materials. For continuous outcomes, we collected the Hoehn and Yahr (HY) stage.
Fox Insight The February 2020 data was downloaded from https://foxden. michaeljfox. org. The demographic and disease status data were obtained from enrollment and registration questionnaires. For clinical outcomes of interest, we obtained the responses from the following questionnaires: Geriatric Depression Scale (GDS) for depression (score of six or higher);  19  Non-Motor Symptoms Questionnaire (NMS-QUEST) for constipation, depressed mood (Mood depressed) and a proxy for lack of the sense of smell/taste;  20.
Cox regression models were used, adjusting for the same covariates as those used in the baseline models. Any outcomes with fewer than 20 events over the follow-up period were not analyzed. The R model statements for these analyses are summarized in the Supplemental Materials. Then, we combined the cohort-level results with an inverse variance-weighted random-effect model. We focused on robust associations throughout the cohorts; therefore, meta-analyses with p-values less than 0. 05 for a test of homogeneity were excluded from further evaluations. Any associations with a two-sided p-value of 0. 05, after Bonferroni-correction for the number of total analyses, were considered significant. For the analysis of the Fox Insight dataset, we tested two terms: the mean difference between males and females (main term) and the interaction between sex and disease duration (interaction term).
The adjusted covariates were linear and square age, linear and square disease duration, and indicators of levodopa and dopamine agonist usage. We further analyzed the association between sex and outcomes among non-PD participants, adjusted for linear and square age. Then, we conducted a test of homogeneity between sex-associated differences identified among PD cases and non-PD participants, to evaluate whether the sex differences were PD-specific or reflected differences observed in the non-PD population. In the analyses for this dataset, we used a significance level of 0. 05 for the raw p-value because the purpose of these analyses was to evaluate consistency with the longitudinal analyses. All the statistical analyses and drawings were executed using R version 3. 6 and python version 3. 7.
59 [0. 48, 0. 73], P = 4. 6E-7, Supplemental Material). This association remain significant when we further adjusted for the baseline MoCA score (HR 0. 56 [0. 37, 0. 86], P = 0. 007) or the baseline MMSE score (HR 0. 67 [0. 51, 0. 90], P = 0. 007, Supplemental Material) at the significance level of 0. 05. Additionally, the baseline MoCA scores were higher in female patients (0. 63 [0. 27, 1. 00]) than in male patients, whereas the baseline MMSE score was not significantly different between sexes (P = 0. 97, Supplemental Materials). Female patients presented with a higher rate of developing dyskinesia (HR 1. 29 [1. 16, 1. 44]). To assess the impacts of weight, body mass index (BMI) and medication on this association, we conducted ad hoc analyses on a subset of data (PDBP, PPMI, and NET_PD_LS1: 2,281 participants) for which height at baseline, weight at baseline, and medication at visits were recorded.
11 [-0. 16, -0. 06] per year, in the z-score). In the raw scores, the sex-associated difference (female-male) in rate of change in MDS-UPDRS total score (female-male) was -2. 7 [-3. 47, -1. 95] (P = 2. 3E -12) and that of the original UPDRS total score was -0. 91 [-1. 33, -0. 49], (P = 2. 66E-05). When only considering the de novo cohorts, similar results were reported for UPDRS part III, with a slower progression rate in female patients than in male patients (-0. 14 [-0. 21, -0. 07] in z-score per year, P = 2. 6E-5, Supplemental Materials). This was corresponding to -1. 59 [-2. 47, -0. 71 Finally, female patients also had lower scores on the UPDRS Part III and the UPDRS total score compared with male patients during the baseline analyses. When analyzing similar phenotypes within the Fox Insight dataset, we generally confirmed the results of the longitudinal dataset analyses (Table  3 ).
In the Fox Insight dataset analysis, the interaction terms between sex and disease duration indicated the average sex-associated differences in the longitudinal trajectories for the outcomes. For example, a positive association for the interaction between disease duration and PDAQ-15 indicated that the PDAQ-15 scores for female patients were higher than those in male patients (i. e. , better cognition-related instrumental functional abilities) among patients with longer disease durations in the Fox Insight dataset. To illustrate this, we visualized the sex differences, stratified by disease duration (Supplemental Materials). The results are consistent with those for the longitudinal dataset analysis, indicating that female patients had a lower risk of developing cognitive impairments during the disease course.
Similarly, the results from the Fox Insight dataset were consistent with the increased rate of dyskinesia development among female patients compared with male patients, and the lower scores and a slower deterioration rate in UPDRS Part II among female patients, as observed in the longitudinal analyses. In addition, null differences between male and female patients in the presentation and progression of wearing off, depression, and hyposmia were also supported by the Fox Insight dataset. In contrast, the loss of the sense of smell/taste was significantly more frequently reported in males among the control participants. Having PD might diminish the general sex difference associated with this phenotype. Single question answers for RBD and some NMSQuest questionnaire questions regarding "difficult to stay awake" (NMSQ_Awake), "difficulty in getting to sleep" (NMSQ_Sleep), "feeling sad, low or blue" (NMSQ_Feel), and NMSQ_Constipation were significantly different according to sex in the Fox Insight dataset.
The prevalences of similar outcomes, such as possible RBD, daytime sleepiness, insomnia, depression, and constipation, were not significantly associated with sex in the meta-analyses of 12 longitudinal cohorts. However, the test for these associations gives raw pvalues less than 0. 05, with the same directions as the Fox Insight results. The primary analyses may not have included large enough sample sizes to detect these associations. All of the sex-phenotype associations among PD participants, not significant in the longitudinal dataset but significant in the Fox Insight dataset, were also significant among non-PD participants. In addition, based on the test of homogeneity between the results from PD and non-PD participants, suggesting that the magnitudes of these sex-associated differences in PD participants did not differ from those in non-PD participants.
Discussion We analyzed clinic-based, longitudinal data from 5,946 participants and meta-analyzed the differences in presentation and progression of phenotypes between men and women with PD. We also used web-based, online cohorts and analyzed data from 17,719 PD patients and 7,588 non-PD participants to confirm our results. The results suggested that female PD patients develop dyskinesia early, progress more slowly with respect to ADL restrictions, and are less likely to develop cognitive impairments. For some non-motor symptoms explored in the online questionnaires (such as possible RBD, daytime sleepiness, insomnia, depressive mood, and constipation), we found significant sex-associated differences among PD participants, only in the Fox Insight dataset. These unconfirmed sex-associated differences may not be specific to PD, as we also observed the same associations in the non-PD participants.
7] [28]  The slower development of cognitive impairment observed in female patients may reflect their relatively high baseline abilities in the areas that are susceptible to PD, although the baseline MoCA score nor MMSE score were able to completely explain the association between sex and the development of cognitive impairment in the current data. Several associations that were previously reported were not observed in the current analysis. RBD was reported to be more prevalent in males with PD than in females with PD, 9,10 although some studies have disagreed. 29, 30 We were unable to confirm this association in the current longitudinal dataset. Although the prevalence of possible RBD, as detected by single-question screening was higher in male patients among the Fox Insight cohort, a similarly increased prevalence in possible RBD for non-PD male participants makes the PD-specific nature of this association questionable.