dataesr/scientific-paragraphs-categorization huggingface dataset:
However, as can be seen from Table  1 , the performance when the optimal rank is used and the component of interest is selected automatically is slightly lower compared to an age-dependent rank. This reduction in performance is due to the fact that the procedure to select the component of interest is more likely to fail for a higher number of components. From the data presented in Table  1  we can see that the performance gradually decreases if a rank higher than two is used. This finding suggests that for the majority of the recordings in the current database a lower rank is more appropriate. Nevertheless, this performance reduction can also be partly attributed to the more difficult component selection for higher ranks. There are various possible explanations for the need for a higher rank for recordings at term-equivalent age.
First of all, it is likely that this is due to the increased amount of artifacts in near term EEG recordings. It is expected that an older neonate will move more, which could lead to more severe distortions and lower quality of the EEG signal. The higher performance for higher ranks in noisy preterm EEG recordings confirms this reasoning. Secondly, the emergence of four distinct sleep states around 36 weeks PMA might also play a role in this phenomenon  [4]. The performance of the described algorithm is lower compared to state-of-the-art algorithms  [13, 14, 34]. However, there are multiple advantages of the proposed method. The major advantage of the algorithm is that it is data-driven and unsupervised. As a consequence, the method can be easily applied on a completely new dataset and used in new centers, where there is little expertise about EEG sleep labelling.
Moreover, in this study the algorithm is assessed on eight channel EEG recordings measured using the restricted 10-20 system for neonates. However, the same approach can also be applied on datasets with fewer or more electrodes without adjustments. Finally, the tensor decomposition can be updated in an efficient way whenever a new batch of EEG data is available  [35]. This allows real time tracking of neonatal sleep states. The main weakness of this study is the lack of a method to define the rank for each new EEG recording automatically in a data-driven way. This is a general issue in tensor applications, therefore it is suggested to combine different tools to asses the rank  [36, 37]. We tested several diagnostics, but none of them resulted in a reliable estimate of the number of components.
Acknowledgments: Research supported by  Bijzonder Onderzoeksfonds KU Leuven (BOF) : The effect of perinatal stress on the later outcome in preterm babies #:  C24/15/036. European Research Council : The research leading to these results has received funding from the  European Research Council  under the European Union's  Seventh Framework Programme  (FP7/2007-2013)/ ERC  Advanced Grant: BIOTENSORS (n°339804). This paper reflects only the authors' views and the Union is not liable for any use that may be made of the contained information. Mario Lavanga  is a SB PhD fellow at Fonds voor  Wetenschappelijk Onderzoek-Vlaanderen (FWO) , supported by  Flemish government.
Unspecific bindings were blocked in 5% non-fat dry milk (Santa Cruz) in TBST 1× (20mM Tris, 137mM NaCl, 0. 1% Tween 20) for 1 hour at room temperature; membranes were then incubated at 4 °C, overnight, with primary antibody diluted in 4% milk (Sigma) in TBST. The SRF (Santa Cruz) and GAPDH (Santa Cruz) antibodies, diluted to 1:1000 and 1:10000, respectively, were used. After washing in TBST, membranes were incubated for 1 hour at room temperature with HRP-conjugated antimouse or anti-rabbit secondary antibodies (Biorad) diluted 1:10000 in TBST, and signals were detected using ECL reagent (Cyanagen). Intensity of Western blot signals was quantified by using ImageLab software.
Protocol design and voluntary exercise Both KO and WT mice were divided into two groups of four mice each for every experimental set: (1) control or sedentary mice (C); (2) mice subjected to voluntary training (E). The latter were installed in individual cages equipped with a wheel (BIO-ACTIVW -Bioseb, France) connected to a digital counter of wheel revolutions and time of the exercise (Figure  1 B ). Data were recorded daily for a period of 3 weeks. 28 The evaluation of the physical performance of the mice took place at 4 moments: just before the beginning of the protocol (T0) and 1, 2 and 3 weeks after the beginning of the training protocol (T1, T2, and T3, respectively) (Figure  1 B ). These evaluations were carried out in the facility "Performance & Metabolism in Mice" (PMM, EA7329, Paris Descartes University).
Statistical analyses Data were expressed as mean ± standard deviation (SD). All statistical analyzes were performed using the software R (3. 4. 4) (R Foundation for Statistical Computing, Vienna, Austria). After assessing variance homogeneity with levene test, statistical analyzes were performed using the linear mixed-models approach (nlme package) with repeated measures ANOVA to evaluate interactions between the training (C vs E) and the genotype (WT vs KO) effect during the protocol (T0, T1, T2 and/or T3). Post-hoc analyses were conducted with simultaneous tests for general linear hypotheses (emmeans package). The statistical significance threshold was set at p <0. 05.
Acknowledgments We thank  Pr Arnaud Ferry  ( INSERM U974 ,  Institut de Myologie ,  CNRS FRE3617 ,  UPMC ,  Université Paris Descartes ,  Sorbonne Paris Cité ) for his outstanding technical support. We acknowledge the technical facility " Performance & Metabolism in Mice" (PMM, IRMES, University Paris Descartes, Sorbonne Paris Cité -INSEP, Paris, France ) for performance and metabolic analysis.
Funding DC is funded by  AFM  ( 2017-20603 ), EFEM 2016, IBPS (2014),  NIH  ( 2013-1R01CA108857-01subcontractor ) and  UPMC Emergence  ( 2011-EME1115 ). DC and AS were funded by  ANR  ( 2013-J13R191 ). This research was also supported by labex  GR-Ex. The labex  GR-Ex , reference  ANR-11-LABX-0051  is funded by the program " Investissements d'avenir " of the  French National Research Agency , reference  ANR-11-IDEX-0005-02.
Methods: A multistage approach was undertaken. A systematic literature review (SLR) was completed to identify studies describing realworld outcomes in patients with nAMD treated intravitreally with aflibercept or RBZ. A metaanalysis of data identified in the SLR generated a pooled estimate of the effectiveness of intravitreally administered aflibercept and RBZ at 52 weeks and an estimate of treatment burden (injection frequency and monitoring). The impact of treatment effect modifiers, such as baseline visual acuity (VA) and age, were corrected through a multivariable meta-regression. A Markov state transition model was developed to estimate the real-world cost-effectiveness of intravitreally administered aflibercept using results from the pooled estimates for effectiveness and treatment burden as primary inputs.
In a recent meta-analysis of studies on intravitreally administered aflibercept, researchers included subgroup analyses describing outcomes in RCTs and observational studies  [17]. The mean VA gain at 12 months in the observational studies was lower but comparable to the gain observed in RCTs. The analysis also suggested that VA improvements were slightly higher with regular dosing ([ 7 injections/year) than with irregular dosing. The cost-effectiveness of intravitreally administered aflibercept and RBZ to treat patients with nAMD in the European setting was established primarily on the basis of data from RCTs  [18] [19] [20] [21] [22]. Both intravitreally administered aflibercept and RBZ have been shown to be cost-effective treatment options in different settings, but no analysis of the real-world costeffectiveness of these two treatments has been undertaken.
Meta-Analysis A meta-analysis of the data identified from the SLR was undertaken. Inclusion criteria for the meta-analysis were studies of treatment-naive patients with nAMD who received intravitreal treatment with aflibercept or RBZ, reported 52-week effectiveness outcomes, and included at least 40 patients per study. The primary objective of the meta-analysis was to derive a pooled estimate for the variables of patient characteristics (age and baseline VA), treatment burden (defined as mean number of injections and injection/monitoring visits from baseline to week 52), and effectiveness (defined as VA change from baseline to week 52 in Early Treatment Diabetic Retinopathy Study (ETDRS) letters). These variables were identified as key parameters in a previous meta-analysis of realworld outcomes with anti-VEGF therapy  [10].
When studies did not report the standard deviation (SD) necessary for the meta-analysis, these values were imputed via the Multivariate Imputation by Chained Equations (MICE) algorithm  [25]. When necessary, variables of interest were converted: number of eyes to number of patients, subgroup mean and SD to aggregate mean and SD, logMAR and decimal to ETDRS letters, SD logMAR to SD letters , P value to SD [via T value and standard error (SE)], confidence interval (CI) to SD [via standard error (SE)], and SE to SD. Fixed-effects and random-effects models were used to produce estimates for all dependent variables. Heterogeneity was assessed using the I 2 statistic  [26] , and model selection was based on the Bayesian information criterion (BIC). Meta-analyses were performed using the Metafor R package  [27]  and the MICE algorithm in R  [25]  (for multiple imputations).
Because the meta-analysis did not provide resource use beyond 52 weeks, injection frequency data for this model were derived from two French studies, Duval et al. [31]  for intravitreally administered aflibercept (assumed constant use for years 2-5) and Boulanger-Scemama et al. [32]  for RBZ. Base-case utilities were derived from published literature. Czoski-Murray used contact lenses to simulate the effects of visual impairment caused by nAMD and estimated a linear relationship between best-seeing eye VA (log-MAR) and time trade-off (TTO) utility  [33]. This was used to estimate utility values for model VA health states using the following equation:.
Meta-Analysis The 72 publications identified in the SLR were additionally screened to assess if the publication reported data on the minimum set of variables necessary to conduct the meta-analysis. The publications (observations) had to describe studies conducted in treatment-naive populations, report data on injection frequency and treatment outcomes (VA change from baseline) at week 52, include at least 40 patients and, in the case of abstracts, be published after 2014. Additionally, publications were screened to identify and remove duplicates. If two or more publications reported data from the same source/population, only one publication was selected and included in the meta-analysis. Publications reporting data on more variables or in larger populations were preferred (Fig. 1 ). After review, 24 observations from 23 studies were selected for inclusion in the meta-analysis (7 observations for intravitreally administered aflibercept  [12-16, 34, 35]  and 17 for RBZ  [34, [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] ) (Appendix 1 in the supplementary material).
Baseline values were defined on the basis of pooled data from the RBZ group (mean age 77. 28 years; mean baseline VA 52. 81 ETDRS letters). After correcting for age and baseline VA, the mean VA gain for patients treated intravitreally with aflibercept was 6. 57 ETDRS letters, with patients receiving 7. 10 intravitreal injections in the first 52 weeks. The mean VA gain for RBZ-treated patients was 4. 42 ETDRS, with patients receiving 5. 88 injections in the first 52 weeks. Using the meta-regression results, it was possible to calculate the impact of injection frequency and treatment (intravitreally administered aflibercept/RBZ) on VA gain and determine the resources needed to achieve clinically meaningful outcomes. Our analysis showed that patients treated intravitreally with aflibercept can achieve a clinically meaningful improvement in VA of 5 ETDRS letters (1 line of vision) with 5-6 injections, whereas RBZ-treated patients would require 6-7 injections to surpass the 5-letter gain versus baseline.
[36] , Gillies et al. [41] , Finger et al. [43] , Gungel et al. [44] , Inoue et al. [45] ). (See Appendix 1D in the supplementary material. ) The mean gain in VA estimated in this analysis is supported by the results from other RBZ real-world meta-analyses (Kim et al. [10] , Guo et al. [11] ) that estimated mean gains in VA at week 52 ranging between ? 4. 85 to ? 5. 00 letters. These estimates are in line with our findings (mean gain of ? 4. 48 letters). Pivotal studies such as the VIEW trials were useful to establish the cost-effectiveness of intravitreally administered aflibercept and RBZ under RCT-like conditions, demonstrating that the same results can be achieved with lower resource use. This analysis provides new data and an insight into the real-world cost-effectiveness of these anti-VEGF agents.
Furthermore, the metaanalysis and meta-regression relied on published articles and abstracts, which are not free from sample selection bias (e. g. , reporting bias). In addition, the meta-analysis was based on aggregate (mean) data and not patient-level data, so it may be prone to ecological bias (i. e. , the associations found between the variables of interest and outcomes at study level may not be the same at patient level). The multivariable meta-regression is potentially not free from confounding bias; because of the limited number of observations and limited availability of covariates, it was not possible to control for all potential covariates. Despite these limitations, there are several strengths to consider. Study selection in the SLR was based on strict criteria, resulting in a small number of observations; but it provided high-quality data, and the methodology followed recent recommendations, including undertaking an SLR and using multiple imputations and meta-regression.
RBZ-treated patients reported gains in VA versus baseline; however, the magnitude of the gain in VA was not comparable to the VA gains reported in the RBZ pivotal RCT. Intravitreal treatment with aflibercept was associated with better mean VA outcomes and an incremental gain in QALYs compared with RBZ and can be considered cost-effective for the treatment of nAMD in patients in France despite a higher price for each individual intravitreal injection of aflibercept compared with RBZ. any of the authors. This study did not require ethical approval as it did not involve human participants or animal subjects. Data Availability. All data generated or analyzed during this study are included in this published article/as supplementary information files. Open Access. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.
As a pro-survival kinase, CK2 is dysregulated in various cancers and several other pathologies, thereby justifying its potential as a therapeutic target and supporting the efforts towards development of chemical inhibitors as drug candidates  [5] [6] [7]. Most CK2 inhibitors identified during the last two decades are ATP-competitive molecules 8 with one of them, CX-4945 (also known as Silmitasertib), currently investigated in clinical trials 9 (ClinicalTrials. gov identifier: NCT02128282). The common drawback of ATP-competitive inhibitors is their limited target selectivity, as the ATP-binding site is highly conserved among different kinases. In the field of protein kinase inhibitors, the concept of exosites and exosite-targeting modulators emerged as a way of addressing this problem. By definition, exosite targeting.
This approach was previously validated using three kinase exosites for which well-characterized ligands are known  [25] [26] [27]. We found that the use of the fumigated models instead of the original crystallographic apo-structures improved both scoring and ranking of the active compounds in the hit list. The fumigation procedure was applied to the CK2β-binding interface of two crystal structures of human CK2α (PDB IDs 3bw5 (formerly 1ymi)  14, 28  and 1na7  29  ) and two homology models built from Zea mays CK2α (PDB IDs 1m2r  30  and 1om1  31  ). These four models represented different degrees of openness of the binding site, controlled by the backbone positions of the loop V101-P109, in human sequence numbering, with PDB 1na7 being the most closed and PDB 1om1 being the most open (Fig. 1a ).
These models were still included in further calculations for completeness. After visual inspection, the four best models (one for each X-ray structure) were selected for virtual compound screening. Virtual screening against multiple fumigated pocket conformations identified potentially active compounds. A database of more than 2 million commercially available compounds was screened against the four fumigated pocket models using the ICM VLS module, with all compounds scored and rank-ordered in all four binding site models. As the ICM docking scores were optimized to distinguish strong binders from the inactive molecules, the compounds with low negative binding scores were prioritized to be tested for biological effects in vitro and in vivo. The two models based on PDB IDs 1mr2 and 3bw5 appeared to be more productive, i.
S5. In addition, STD-NMR was used to analyze the competition between compound 4 and AMPPNP, a non-hydrolysable ATP analogue. As shown in Supplementary Fig. S8c , AMPPNP is not displaced upon compound 4 binding, thus confirming that this inhibitor does not bind in the ATP binding site. Crystal structure of CK2α-4 and CK2α-6 complexes. Crystal structures were determined of both 4 and 6 bound to the CK2β binding site on CK2α (pdb: 6FVF and 6FVG). To accommodate the compounds, the β4-β5 loop moves out to open up the pocket compared to the apo structure (pdb: 5CU6)  37. As predicted by modeling and suggested by the STD analysis, the hydrophobic ring of the indole from 6 and 4 bind in the pocket occupied by Phe190 of the CK2α:CK2β complex (Fig. 3a-c ). Indeed, the crystal structures of 4 and 6 show a very good alignment of the indole and the phenyl ring from the CK2 complex (pdb:4DGL)  23.
The hinge region interacts directly with the adenosine moiety of ATP in the apo structure (pdb:5CU6 supplementary Fig. S13c ), and its movement therefore disrupts the hydrogen bonding network with ATP. Displacement of hinge binding compounds (e. g. ATP) has been observed in association with a unique closed conformation of the αD loop  37. Therefore, this is a likely mechanism by which the αD loop is forced into the closed position. However, it may also be that the movement of the β4-β5 loop directly causes the αD loop to adopt the closed form which in turn leads to the displacement of ATP. Whichever mechanism is in operation, the resulting displacement of ATP may account for the mixed-competitive mode of inhibition with respect to ATP and the lower K i for CK2α than for the CK2α-ATP complex that was observed for these compounds.
Evaluation of model druggability with ICM PocketFinder. Interface druggability was evaluated by the ICM PocketFinder algorithm  32  as implemented in ICM version 3. 5. The algorithm starts by calculation of the Lennard-Jones potential around the protein a 3D grid with 1 Å step size. The grid map value at point r is given by: where the sum is taken over all atoms a in the system, d(a, r) is the distance from atom a to the grid point r, and the atom-dependent parameters A a and B a are taken from the Empirical Conformational Energy Program for Peptides (ECEPP)/3 molecular mechanics force field. Map values P 0 (r) are truncated at -0. 8 kcal/mol to retain only the attractive regions. ∑ =     -     P A d a B d a r r r ( ) ( , ) ( , ) (1) Next, Gaussian convolution of the potential P 0 at each grid point r is performed by: x r P d P d r x x ( ) 1 exp( ( , ) ) ( ) , 2 6Å (2) 3 2 2 0 ∫ λ λ λ = - =.
where d(x, r) is the distance between grid points x and r. The resulting map P(r) is contoured using an in-house algorithm to produce envelopes whose location, shape and volume were indicative of the ligand binding pockets. Interface pocket model generation by fumigation. Two X-ray structures of human CK2α (PDB IDs 3bw5  28, 56  and 1na7  29  ) and two homology models built from Zea mays (PDB IDs 1m2r 30 and 1om1 31 ) were used as the starting points for pocket simulations. For each model, its largest possible pocket volume was approximated by a space density calculated as follows: 1. Simultaneous conversion of pocket side-chains (except Ala, Gly, and Cys) to Ala, 2. Construction of atom density map for the obtained "shaved" protein on a 0. 5 Å 3D grid by ∑ =       -       D e xp d a w r r ( ) ( , ) (3) a a 2 2 Here w a is the Van der Waals radius of atom a.
Virtual ligand screening. From the pocket conformation ensembles generated by the fumigation algorithm, four interface models were selected for Virtual Ligand Screening. Each model was converted into a set of potential grid maps, and a database of 2,285,435 commercially available compounds (Molcart, Molsoft LLC) was screened against them using standard ICM virtual screening protocol as implemented in ICM version 3. 5. Top 100 compounds were selected for experimental validation.
Images were analyzed and band intensities were quantified using ImageJ software. Primary antibodies were GAPDH antibody from Ambion, PARP and HSP90 antibodies from Cell Signaling, survivin antibody from Novus biologicals, p21 antibody from Santa Cruz Biotechnologies, p21-(phospho-Thr145) antibody from Abcam. Secondary antibodies were peroxidase-conjugated affinity pure Goat anti-rabbit IgG (#111035003) and peroxidase-conjugated affinity pure Goat anti-mouse IgG (#115035003) from Jackson Immuno Research. Live cell tracking. Cells grown on 96-well flat-bottomed plates (Corning Falcon) were tracked using an Essen IncuCyte Zoom live-cell microscopy instrument, an automated live cell imager with high-throughput capabilities and built-in data analysis. Experiments were conducted at 37 °C and 5% CO 2.
The software incorporated into the IncuCyte Zoom was used to analyze the images. Cell proliferation. MCF10A and MDA-MB231 cells were seeded into 96-well plates at a density (1 × 10 4 and 2 × 10 4 cells/well, respectively) and allowed to attach overnight. Bright field images were captured every 3 h for the duration of the experiment. The detection software was calibrated specifically for MCF10A and MDA-MB231 to ensure accurate distinction of cells from empty space. Cell proliferation data were obtained by the cell confluence increment in each of the treatments and expressed as percentage relative to that of control cells. Cell migration. Cells seeded at equal density were allowed to grow to confluence overnight. The Essen Bioscience WoundMaker TM , an accessory for the IncuCyte Zoom ® , was utilized to create Scratch-wounds of a standardized width (~600 μm).
5 mM MES pH 6. 5, 35% glycerol ethoxylate and 180 mM ammonium acetate in a 1:1 ratio with a total volume of 2 μL by the hanging drop vapour-diffusion method. The compounds were soaked at at 10 mM into these crystals for 15-20 h in 107 mM MES pH 6. 5, 35% glycerol ethoxylate and 1. 04 M ammonium acetate after which the crystals were cryo-cooled in liquid nitrogen for data collection. The crystals were cryo-cooled in liquid nitrogen in the same solution for data collection. X-ray diffraction data was collected at the Diamond synchrotron radiation source, then processed using the pipedream package by Global Phasing Ltd; structures were solved by using programs from the CCP4 package. Models were iteratively refined and rebuilt by using AutoBuster and Coot programs. Ligand coordinates and restraints were generated from their SMILES strings using the Grade software package.