dataesr/scientific-paragraphs-categorization huggingface dataset:
Again, in this analysis, we observed that patients without vitrectomy and/ or focal/grid laser procedures also reported a higher discontinuation rate with longer injection interval at 24 months, so that possible resolution of DME following vitrectomy and/or focal/grid laser procedure does not appear to be the driver of increased discontinuation in the longer injection interval group. Further research should be conducted in databases that contain clinical and/or patient-reported outcomes, and/ or treatment strategies, to determine the The log-rank test for equality of survival functions indicates differences between treatment interval groups. VEGF, vascular endothelial growth factor reasons for greater treatment discontinuation in patients with longer treatment intervals, which was not possible in the current analysis.
The strength of our study includes an analysis population from a large database with over 1700 patients with DME receiving anti-VEGFs in a routine clinical care setting from the USA with a long follow-up time of several years. However, a few limitations of this study should also be considered. MarketScan is a US-based claims database that contains information on patients enrolled in health insurance programs  [17, 28]. This makes it reliant upon the accuracy of the medical coding and billing information. Thus, medication use may be overestimated in such databases, since drug prescriptions are used as a proxy for medication use; furthermore, the analysis may also be affected by unobserved differences between patients, and deceased patients may remain in the dataset for a certain period. Also, in our analysis it was not possible to distinguish between patients treated unilaterally or bilaterally, which was addressed through the exclusion of patients with consecutive treatments within 15 days.
Steffen Andersen is currently an employee of Novo Nordisk A/S, Denmark. All authors attest that they meet the current ICMJE criteria for authorship. Compliance with Ethics Guidelines. Data for this analysis were extracted from the IBM MarketScanÒ Commercial and Medicare Supplemental databases. All enrollment records and inpatient, outpatient, ancillary, and drug claims were collected in accordance with the Health Insurance Portability and Accountability Act (https://www. cdc. gov/phlp/publications/topic/ hipaa. html). As this study constituted of secondary analyses on fully anonymized data, institutional review board or additional informed consent was not required (https:// www. hhs. gov/ohrp/regulations-and-policy/ regulations/45-cfr-46/index. html). Data Availability. The datasets generated and analyzed during the current study can be made available upon reasonable request, which may require a data access fee paid to Merative (Healthcare Data, Technology and Analyt-ics|Merative).
The data for this study consisted of anonymised patient-level data taken from the Merative MarketScan Ò Commercial and Medicare Supplemental databases https://www. ibm. com/products/marketscan-research-databases/databases. Data were stored and analyzed securely in Novartis' in-house Data42 platform under a license from Merative. Open Access. This article is licensed under a Creative Commons Attribution-NonCommercial 4. 0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.
ACKNOWLEDGEMENTS Funding. This research was funded by  Novartis Pharma A. G. , Basel, Switzerland. The funder participated in the study design, data analysis, interpretation of the data, preparation, review, and approval of the manuscript, and funded the journal's  Rapid Service Fee. Medical Writing, Editorial, and  Other Assistance. The authors would like to thank  Patrick Ward, PhD ,  Abhishek Srivastava , BTech. and  Sourav Biswas, MTech , in the Real-World Evidence team,  Novartis Business Services CONEXTS  for data analyses;  Ashwini Patil, PhD  of  Novartis Healthcare Pvt. Ltd. , India ,  Susan Browne, PhD , of  Novartis Ireland, Ltd. , and  Divya Sharma ,  MDS of Novartis Healthcare Pvt. Ltd. , India  for medical writing support, under the guidance of the authors and in accordance with Good Publication Practice (GPP2022) guidelines (https://www.
Materials and Methods: This study analysed the kinomic profiles of human EndoC-βh1 cells following vehicle and GLP-1R stimulation with the pharmacological agonist exendin-4, as well as exendin-4-based biased derivatives exendin-phe1 and exendin-asp3 for acute (10-minute) versus sustained (120-minute) responses, using PamChip protein tyrosine kinase and serine/threonine kinase assays. The raw data were filtered and normalized using BioNavigator. The kinase analyses were conducted with R, mainly including kinase-substrate mapping and Kyoto Encyclopedia of Genes and Genomes pathway analysis.
| Matching substrates to upstream kinases Kinase-substrate information was obtained from PhosphoNET, Uniprot and PhosphoSite databases. The top 50 Ser/Thr kinases and 25 Tyr kinases with prediction V2 scores higher than 300 were selected for each phosphosite from PhosphoNET (Supplementary Files 1 and 2; see the supporting information). Kinase-substrate mapping was performed in R.
| Upstream kinase analysis We modified the kinase-substrate enrichment analysis (KSEA) formula  19  to use the average phosphosite log 2 (FC) weighted by the prediction V2 scores for each phosphosite of a given kinase. The modified z kinase score formula is as follows: Z ¼ s w À p ð Þ ffiffiffiffi m p SD s w ¼ P m i¼1 x i Â log 2 FC P m i¼1 x i , where s w represents the weighted mean log 2 (FC) of the substrate subset for a given kinase, p denotes the mean log 2 (FC) of all phosphosites in the raw dataset, m is the number of phosphosite substrates identified for each kinase, SD represents the standard deviation of the log 2 (FC) across all phosphosites and x represents the PhosphoNET predictor V2 score. The scores were assumed to be normally distributed, therefore the P values were determined by one-tail tests to estimate the probability that the real scores were at least as extreme as the measured scores.
| Pathway enrichment analysis To conduct a representative analysis of kinase lists, the 'enrichKEGG' function in R package ClusterProfiler v. 4. 0 was applied to determine whether the kinases identified are enriched within specific pathways. 20 Statistical thresholds of P less than. 05 and q-value less than 0. 05 were chosen to select significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) terms and pathways. A dot plot of the top 10 KEGG terms and pathways, ranked by kinase ratio and coloured by adjusted P value, was created. A Venn diagram was generated to identify the kinases shared within these pathways using Venn webtools (https://bioinformatics. psb. ugent. be/webtools/Venn/), with a list of kinases illustrated.
| RNA-seq database analysis High-throughput sequencing data were retrieved from Gene Expression Omnibus (GEO) databases to assess the level of expression of specific kinase genes. Gene expression data from the EndoC-βH1 cell line were obtained using GEO accession GSM3333914. Additionally, raw read count values of 18 non-diabetic and 39 T2D islet samples from the GSE164416 series were analysed using DESeq2 21 in order to compare differentially expressed kinase genes, followed by integration with our kinomic analysis results.
To assess this, we modified the KSEA formula  24  to consider the affinity of individual kinases towards binding to specific substrates. In this way, kinase scores were calculated to determine the degree of specific downstream kinase activity changes following GLP-1R stimulation. Here, we present a list of kinases that showed significant activity changes compared with vehicle exposure under at least one of the conditions tested (Figure  2B, C ). All the identified kinases were confirmed to be expressed in EndoC-βh1 cells at the mRNA level (GSE118588  25  ). Consistent with our substrate phosphorylation results, more pronounced changes were detected in Tyr kinase activity after sustained versus acute GLP-1RA exposure (Figure  2B ). For STKs, responses were more variable and presented marked changes over vehicle conditions in both acute and sustained experimental groups (Figure  2C ).
| Pathway analysis reveals key kinases involved in GLP-1R downstream signalling To further understand the impact of changes in individual kinase activity on global beta cell kinase networks, we performed pathway enrichment analysis for those kinases showing significant activity changes downstream of GLP-1RA stimulations. The top 10 relevant KEGG pathways were sorted by kinase ratio, as shown in Figure  3A, B ; we focused on the first three pathways from each kinomic dataset. The mitogen-activated protein kinase (MAPK) signalling pathway was highlighted as the most enriched pathway for both PTK and STK analyses, in agreement with previous reports linking MAPK family activities to pancreatic beta cell function. 27 For instance, PKA-activated MAPKs play a crucial role in accelerating the cell cycle, which is associated with maintenance of beta cell mass.
To provide more detailed evidence for the regulation of the pathways involved, a systems biology approach was conducted and depicted using STRING v. 11. 0 (https://string-db. org) to analyse interactions amongst the three top-related kinases pathways for Tyr kinases (Figure  4C ) and within the MAPK signalling pathway for Ser/Thr kinases (Figure  4D ). These analyses showed that the selected pathways were highly overlapped and correlated, although some kinases may act independently from others. Specifically, most PTKs can be linked to JAK2, FGFR2 and JAK3 (Figure  4C ), while BRAF and PRKCB were the most centred among the STKs (Figure  4D ), suggesting that they may play important roles in regulating beta cell-biased GLP-1RA responses. As pancreatic beta cells constitute more than 50% of the mass of human islets,  3  we additionally confirmed expression of the kinases assessed in this study in a human islet RNA-seq database that contained 18 non-diabetic and 39 T2D islets (GSE164416 30 ) (Figure  S3 ).
Kinases are activated by phosphorylation, which subsequently activates a cascade of events resulting in the phosphorylation of specific amino acids within substrates. 31 Different databases have been designed to recognize kinase-specific phosphosites to facilitate the elucidation of phospho-signalling networks. For example, the PhosphoSite database and NetworKIN predictions are recommended for KSEA. 19 Here, we used the PhosphoNET database, which predicted more than 300 kinases for our substrates. By weighting the prediction V2 score, we were able to assess the influence of the different kinases in the degree of phosphorylation of each substrate. Although our substrate peptides are comparatively well conserved, public databases are mainly generated based for human kinases. Therefore, currently this method of analysis may only be suitable for human cell lines such as EndoC-βh1.
Future verification of key kinase activity and kinetic profiles by Western blot and FRET-based assays, followed by corresponding mechanistic investigations of the functional consequences of modulating specific kinase activities using RNAi or chemical inhibition approaches, will be necessary to fully elucidate the kinase signatures of GLP-1R biased versus balanced compounds. Furthermore, liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis following co-immunoprecipitation, or proximity ligation assays, could assist in the identification of specific substrates downstream of the identified kinases. It is worth mentioning that our kinase database would be suitable for the analysis of kinomic profiles from any human cell line using the same substrates. However, as our kinase profiling is based on predicted peptide phosphorylation levels using literature databases, an obvious limitation of the present study is that kinase signalling may be different in vivo, as well as in primary islets.
ACKNOWLEDGEMENTS The authors thank  Prof. Amar Abderrahmani  for assistance during raw data acquisition. This work was supported by  MRC  grant number  MR/R010676/1  to A. T. , B. J. , G. A. R. and P. F. , as well as by  UKRI COVID-19 Grant Extension Allocation  (coA) to A. T. A. T. also acknowledges further support from the  EFSD, Diabetes UK, Eli Lilly , the Commonwealth and the  Integrated Biological Imaging Network (IBIN).
, 1996; Summerfield & Hulton, 1994; Syvitski & Milliman, 2007; Syvitski et al. , 2005). When considering the total ice-free continental surface, this is also equivalent to an average denudation rate of ≈60 mm kyr -1 (e. g. ,  Wilkinson & McElroy, 2007). Bridging these very different time spans, the production of cosmogenic nuclides in the upper few meters of the Earth's surface rocks provides a powerful tool for quantifying denudation rates that integrate the last 10 2 -10 5 years  (Gosse & Phillips, 2001; von Blanckenburg, 2005). In river catchments, this technique is <30-years old, but the global database is growing and covers more and more different climatic and geodynamic contexts  (Codilean et al. , 2018 (Codilean et al. , , 2022;; Portenga & Bierman, 2011). For the period 1995-2021, 4,425 measurements of in situ produced 10 Be concentrations are included in the Octopus database  (Codilean & Munack, 2021) , leading to a worldwide median value of about 70 mm kyr -1 , and ranging from a few mm kyr -1 to a few mm yr -1 as in highly dynamic settings like Taiwan (e.
Once distributed over the worldwide surface of croplands (≈1. 9 × 10 9 ha; e. g. ,  Croplands, 2022) , the annual loss estimated by  Borrelli et al. (2017)  converts into rates of recent surface erosion of about 1,300-1,500 mm kyr -1. This is in line with a global database including >1,500 runoff plots  (Xiong et al. , 2019) , which indicated that anthropogenically disturbed lands such as croplands and orchards are characterized by mean soil losses that are roughly 6 to >100 times the typical values generally measured for undisturbed, natural lands. To gauge human-induced disturbance on the normal functioning of catchment, cosmogenic nuclides, predominantly in situ produced 10 Be, have long been considered for establishing predisturbance (or natural) denudation rates that can be compared to other proxies such as sediment yields derived from gauging stations  (Bartley et al.
This study also received financial supports from the CEREGE laboratory (APIC Research project). The ASTER AMS national facility (CEREGE, Aix-en-Provence) is supported by INSU/CNRS, the ANR through the Projets thématiques d'excellence programme for the Equipements d'Excellence (ASTER-CEREGE action), the IRD, and the University of Aix-Marseille. Lionel Siame is grateful to IRD for the continuing support through the "Mission de Longue Durée" mobility program. The authors warmly thank Veerle Vanacker and Michel Brossard, as well as an anonymous reviewer, for their thorough reading and very helpful comments on a draft of the manuscript. We also thank the editorial team of Earth's Future for the efficient management of our manuscript during the review and editing process. The authors declare no conflicts of interest relevant to this study.
Acknowledgements This work was financially supported by the  Knut and Alice Wallenberg Foundation (Tail of the sun) , the  EU  project ( ESR 955837_HORATES ), the  Swedish Research Council  ( 2016-06146 ,  2016-03979 ),  ÅForsk  ( 18-313 ),  Academy of Finland Postdoctoral Researcher  (Project Number  340103 ),  EU   H2020 Marie Sklodowska-Curie grant agreement  ( No 101022777 ),  Swedish Foundation for Strategic Research (SiOS) , and the  Swedish Government Strategic Research Area in Materials Science on Advanced Functional Materials at Linköping University  (Faculty Grant  SFO-Mat-LiU No. 2009-00971 ). X-ray scattering experiments were performed at the  NCD-SWEET beamline of ALBA  synchrotron with the collaboration of  ALBA  staff and in particular of  Dr. Eduardo Solano. The authors acknowledge  Prof.
Participants We included participants from two community-based cohorts in which the protocol included cognitive assessments, T1-weighted MR imaging and genotyping. Cross-sectional data from the Saguenay Youth Study (SYS) cohort of 1029 healthy adolescents (mean age = 15. 0 ± 1. 8, 533 females, 496 males) were recruited from a unique population (European ancestry) with a founder effect in the Saguenay-Lac-Saint-Jean region in Quebec, Canada between 2003 and 2012  (Pausova et al. , 2017). Longitudinal data were obtained in IMAGEN participants of mostly European descent (n = 1122; mean ages at baseline (follow-up 2) = 14. 4 ± 0. 4 years (19. 07 ± 0. 75 years), 566 females, 556 males) recruited in local schools at eight sites located in England (2 sites), France (1 site), Ireland (1 site), and Germany (4 sites); these participants had MRI data available for both baseline and the second follow-up.
Genotyping SYS adolescents were genotyped either with the Illumina Human610-Quad BeadChip or the HumanOmniExpress BeadChip. Quality control was performed using PLINK  (Purcell et al. , 2007). Variants were excluded if the call rate was < 95%, the minor allele frequency was < 0. 01 and were not in Hardy-Weinberg equilibrium (P < 1 × 10-6). Haplotype phasing was performed with Shape-IT  (Delaneau et al. , 2008)  using SNPs that underwent quality control, and were present on both genotyping platforms and the 1000 Genomes SNPs in European reference panel (Phase 1, Release 3)  (Genomes Project, 2015). The phased genotype data underwent imputation with IMPUTE2  (Van Leeuwen et al. , 2015) , and variants with either a low imputation quality (information score < 0. 5) or low minor allele frequency (< 0.
PGS-NP Calculation To index a PGS-NP, we started by selecting Gene ontology (GO) terms associated with neuronal plasticity, as well as those associated with long-term depression and long-term potentiation; the latter two processes are common experimental models of synaptic plasticity across the mammalian brain  (Malenka and Bear, 2004). This was achieved by using Gene Ontology Browser on the Mouse Genome Informatics (http://www. informatics. jax. org/). Using this browser and the three relevant terms (i. e. , "neuronal plasticity", "long term potentiation", "long term depression"), we identified a total of 26 GO terms categorized in molecular function (18 of neuronal plasticity, 4 of long-term depression and 4 long-term potentiation, Supplementary Table  2 ). To extract genes associated with these 26 GO terms, we used the curated databases of the web-based tool QuickGO  (Binns et al.
, 2018)  to assign an effect size to each of the "neuronal plasticity" SNPs. Although two GWASs assessed cognitive performance and intelligence, these studies had substantially smaller samples (257, 841  (Lee et al. , 2018)  and 269,867  (Savage et al. , 2018) , respectively) than the GWAS on educational attainment. In addition, a review of the literature notes the strong genetic correlation that exists between educational attainment and cognitive abilities  (Malanchini et al. , 2020). The intersection of the 10. 1 million SNPs from the educational attainment GWAS with the 155,600 SNPs associated with the "neuronal plasticity" genes yielded a total of 40,804 SNPs to which effect sizes were assigned based on the summary statistics from the educational attainment GWAS  (Lee et al. , 2018). The list of these SNPs with the corresponding summary statistics is available in the following public repository (https://github.
MRI data acquisition and processing In SYS, a Phillips 1. 0-Tesla MRI system was used to acquire T1weighted anatomical images using 3D RF-spoiled gradient echo scan with 140-160 slices, 1-mm isotropic resolution, TR = 25 ms, TE = 5 ms, flip angle = 30 • ). Additional information on the MRI acquisition and processing were previously described elsewhere  (Pausova et al. , 2007). In IMAGEN, 3. 0-Tesla MRI systems by different manufacturers were used to obtain high-resolution T1-weighted anatomical images (Siemens: five sites, Philips: two sites, General Electric: one site). The magnetic resonance protocol and harmonization across sites are described elsewhere  (Schumann et al. , 2010). FreeSurfer (Version 5. 3. ), a fully automated and validated segmentation software, was used to parcellate the cerebral cortex in 68 unilateral cortical regions with the Desikan-Killiany atlas as reference in both cohorts  (Desikan et al.
Inter-regional profiles of cortical thickness We started by evaluating the moderating role of standardized (z scored in each cohort) PGS-NP in the relationship between thickness and cognition in a sex-specific manner. Thus, we tested for a moderating effect of PGS-NP on the relationship (beta regression estimates) between IQ composite scores (predictors) and cortical thickness (unadjusted for age) in each of the 34 (left) cortical regions (dependent variables). We evaluated only regions of the left hemisphere due to the availability of gene-expression data in the Allen Human Brain Atlas (see section on virtual histology for details). We used a non-parametric permutation approach to determine if cognitive performance was interacting with PGS-NP vis-a-vis cortical thickness for each profile of cortical regions.
e. , sum of the 34 beta estimates). After repeating the shuffle and the calculation of the test statistic 5000 times, we calculated the two-tailed p-value of the null hypothesis (i. e. , absence of an interaction) as the proportion of datasets with absolute value of the test statistic >= absolute value of the original test statistic. Because the main hypothesis focused on the influence of plasticity on performance IQ, we ran a similar inter-regional profile analysis for the five performance IQ subtests. To complement IQ-by-PGS-NP interaction analyses, we used a median split of the PGS-NP to divide participants into "High" and "Low" PGS-NP group, sex stratified. The interaction statistics will be reported first in accordance with our hypothesis on the moderating role of the PGS-NP. For each group (e.
Virtual histology A virtual histology analysis was performed as an exploratory analysis on inter-regional profiles capturing the relationship between performance IQ-related scores and thickness. This analysis was performed using the median-split profiles to simplify the interpretation of the results. Briefly, the virtual histology approach used publicly available datasets of gene expression (Allen Human Brain Atlas and BrainSpan Atlas) to extract a list of 2511 genes with consistent gene-expression profiles across individuals in the 34 cortical regions (left hemisphere) of the Desikan-Killiany anatomical atlas  (French and Paus, 2015). Virtual histology was used to test spatial correlations between the strength of the performance IQ-thickness relationship and inter-regional variations of gene expression for nine cell-specific gene panels (i.
Discussion To determine whether neuronal plasticity genes moderate the structure-function relationship between cortical thickness and cognitive aptitudes in the context of experience, we developed a polygenic neuronal plasticity score consisting of genes implicated in neuronal plasticity, as indicated by a curated database. The first objective of this study was to determine whether the capacity for neuronal plasticity, indexed by a polygenic score, moderates the relationship between cortical thickness and cognitive abilities during adolescence. The complementary cross-sectional results from SYS and longitudinal results from IMAGEN supportto some extentthis hypothesis for adolescent males. Although the interaction between performance IQ and PGS-NP was not significant (at p = 0. 06), the overall difference in the correlation coefficients between the two male groups across the 34 cortical regions was consistent with our prediction (i.