dataesr/scientific-paragraphs-categorization huggingface dataset:
See Table  2  for patient demographic details include age and gender. For both the ACTKNOW and PACKNOW cohorts, all patients were PCR-negative for P. vivax co-infection at enrollment, however it was unknown whether the P. knowlesi patients had past exposure to P. vivax parasites. P. vivax has been endemic in Sabah, Malaysia, but the number of malaria cases due to P. vivax has substantially declined from 2009-2017 (whilst the number of cases due to P. knowlesi has risen). 39 In line, the number of patients retrospectively excluded from these studies due to P. vivax infection detected by PCR was 14 in ACTKNOW and only 1 in PACKNOW. All patient data variables are provided in Data S1. We utilised four panels of malaria-naı ¨ve negative control plasma samples as previously described. 9 Briefly, this included 102 individuals from the Volunteer Blood Donor Registry in Melbourne, Australia; 100 individuals from the Australian Red Cross, Melbourne, Australia; 72 individuals from the Thai Red Cross, Bangkok, Thailand; and 96 individuals from the Rio de Janeiro State Blood Bank, Rio de Janeiro, Brazil.
ACKNOWLEDGMENTS We acknowledge the efforts of the original study teams for collecting the P. knowlesi clinical samples. We thank the following organisations for donation of malaria-naive control plasma: the  Australian and Thai Red Cross ; the  Rio de Janeiro State Blood Bank  (with support from  Andre M. Siqueira ); and the  Volunteer Blood Donor Registry at WEHI. We thank  Shazia Ruybal  for support generating an automated quality control platform through R, based on prior work by  Connie Li-Wai-Suen , which was also used for the standard curve conversion. We thank  Sarah Miller  for assistance with ethical approvals. We would like to thank the Director-General,  Ministry of Health, Malaysia , for permission to publish this manuscript. We also acknowledge the  Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.
(A-C) The median IgG level at day 7 (the peak of the response) was divided by the seropositivity cut-off to generate the fold change at the peak compared with the background. The percentage sequence identity was calculated for the protein construct sequence using NCBI BlastP, or the PlasmoDB method when required (see Table1). A Spearman's correlation was performed to determine the relationship of the fold change with the sequence identity using data from all 21 P. vivax proteins, for the (A) ACTKNOW r = 0. 63, p = 0. 0023, (B) PACKNOW cohorts r = 0. 56, p = 0. 0083, and (C) ACTKNOW and PACKNOW combined (median antibody level of n = 134 P. knowlesi patients at day 7 divided by the seropositivity cut-off) r = 0. 69, p = 0. 0006.
Luminescence reads were normalized to those of DMSO-treated controls. Data represent mean ± SD from triplicate independent experiments. g Parental, VEN-RE, and VEN-RE OCI-AML2 and MOLM-13 cells transfected with a control shRNA (shCON) or a shRNA targeting MCL-1 (shMCL-1) that were induced with (solid lines) or without 100 ng/mL doxycycline (dotted lines) and treated with 0-10 μM VEN for 48 h. Cell viability was determined by CellTiter-Glo assay. Luminescence reads were normalized to DMSO-treated control cells. Data are mean ± SD to the baseline levels, suggesting activation of the pathway upstream of MEK (Fig. 4d ). A previous study found that BCL-2 could co-localize with NRAS, resulting in RAS activation,  23  a known upstream activator of MAPK pathway. Of note, expansion of pre-existing RAS-mutant clones was reported recently in VEN-resistant AML pts, in association with monocytic phenotype.
We identified both, transcriptional enrichment of RASregulated genes in VEN-RE cells, the genomic expansion of KRAS and NRAS clones, and increased protein level of MCL-1 and p-ERK in patients progressing on VEN/HMA therapy. Further, we demonstrated that NRAS-G12D expressing BaF3 and MOLM-13 cells became resistant to VEN in vitro and in vivo, and that the inhibition of MCL-1 restored MOLM-13 NRAS-G12D cells sensitivity to VEN. Additional components of MAPK signaling, such as mutations in negative regulator phosphatase PTPN11, were reported by us in AML patients refractory to or relapsing on single agent VEN therapy,  36  similar to expanding clones containing mutations in FLT3-ITD, and upstream regulator of MAPK activity, in both single agent and in HMA combination trials. 36, 37 hese findings indicate the utility of co-targeting MAPK and BCL-2, demonstrated by our group previously  38  and confirmed here in VEN-RE cells by kinase screening tool, the finding that lends support for testing the combinations in clinical trials (NCT02670044, NCT04487106).
Luminescence reads were normalized to those of DMSO-treated control cells. Data represent mean ± SD from triplicate independent experiments. c MOLM-13 cells expressing NRAS-G12D were treated with indicated inhibitor for 24 h, then cell viability was determined by CellTiter-Glo assay. Luminescence reads were normalized to those of DMSO-treated control cells. Data are mean ± SD. d Spleen harvested from mice received vehicle, AZD5991, VEN, or the combination of AZD5991 and VEN. One spleen from a healthy mouse is shown for comparison. e Weight of spleens collected from each group. Data are mean ± SD. f Tumor burden shown by % hCD45 from spleens (SP), bone marrows (BM) and livers from each mouse in specified cohort. Data are mean ± SD. g H&E staining of SP, BM, and liver from one representative mouse from each group tandem repeat DNA fingerprinting in September 2016 by the Cytogenetics and Cell Authentication Core Facility at The University of Texas MD Anderson Cancer Center.
) at an accelerating voltage of 80 kV. Digital images were obtained using the AMT Imaging System (Advanced Microscopy Techniques Corp. ). Seahorse mitochondrial stress assays Cells were seeded with Seahorse medium (Agilent, Seahorse XF medium with 2 mM glutamate, 10 mM glucose, and 2 mM pyruvate) in 96-well Seahorse plates. Plates were centrifuged at 1200 g to settle cells to the bottom of the wells. Mitochondrial stress tests were then performed with 1. 5 oligomycin, 0. 25-2. 5 μM FCCP, and 0. 5 μM rotenone and antimycin on a Seahorse XFe 96 Analyzer (Agilent). Reads were normalized to the viable cell count. A detailed protocol is provided at Agilent's website: https://www. agilent. com/cs/library/usermanuals/public/ insert-xf-pmp-reagent-web. pdf. Data were normalized to per one million cells.
Library size distributions and concentrations were analyzed on a DNA 1000 assay chip using Bioanalyzer (Agilent) and sequenced on an Illumina MiSeq sequencer. The data were analyzed with Tapestri Insights software version 2. 1 (Mission Bio) using default settings. Generation of NRAS-G12D expressing cells GFP + BaF3 or MOLM-13 cells were sorted by flow cytometry 3 days after retroviral infection with NRAS-G12D vector  28  (same virus packing as in inducible shMCL-1 knockdown section). NRAS-G12D expression were induced with doxycycline (1ug/ml) for 72 h prior experiment.
ACKNOWLEDGEMENTS This study is partially supported by  NIH   R01CA235622  (to MK). We acknowledge the  Flow Cytometry and Cellular Imaging Core Facility at MD Anderson Cancer Center and Functional Proteomics Reverse Phase Protein Array Core , supported by  NIH/NCI  under award number  P30CA016672. We acknowledge the Imaging platform of the IRSL for the microscopy ( Universite de Paris). Editorial support was provided by  Amy Ninetto  of  Scientific Publications, Research Medical Library , at  MD Anderson Cancer Center. We acknowledge  Robert Durruthy-Durruthy  ( MissionBio ) for assisting with the single-cell-sequencing data analysis. This work was supported by research grant from  AbbVie ; by  Cancer   Center Support Grant  from the  NIH/NCI ,  P30 CA016672 , and in part by the  NCI Leukemia   SPORE Career Development Award  ( CA100632 ) to VLB.
Data collection In the SEPSISPAM trial, the presence or absence of mottling was assessed by nurses every two hours, from 2 h after the inclusion to the 5 first days or to the discontinuation of catecholamine. In patients weaned from catecholamine for the 5 first days, the presence or absence of mottling was assessed up to 12 h after norepinephrine weaning. Skin mottling was defined as a red-violaceous discoloration of skin on the knee or above it. No information was collected regarding mottling intensity (mottling score). For each patient, we calculated the duration of mottling over the first 24 h after inclusion. Arterial lactate levels were measured at inclusion, 6 and 12 h after inclusion and once daily thereafter. An arterial lactate level lower than 2 mmol/L was considered as normal.
Ethical concerns The SEPSISPAM trial (NCT01149278) was approved for all participating centers by the ethic committee at the Angers University Hospital. Written inform consent was obtained from all patients, their next of kin or another surrogate decision-maker, as appropriate. In accordance with ethics policy, if patients were unable to provide informed consent and the next of kin or a designated person was not available, the emergency inclusion procedure was applied and post hoc consent was obtained from patients who survived.
Statistical analysis Quantitative variables, presented as median [interquartile range] were compared with Mann-Whitney test. Qualitative variables, presented as the absolute value [percentage] were compared with Fisher's exact test. Survival curves were computed by the Kaplan-Meier method and compared by the log-rank test. First, only available data were analyzed, then, we re-analyzed the dataset of mottling, dealing with missing data, assuming that when mottling state was similar around missing data, the mottling state for the missing data was the same (last observation carried forward: LOCF). For instance, if the patient has mottling at H2 and H6, and the data were missing at H4, then the patient was considered with mottling at H4. A mixed model was used to explore the evolution of MAP during the 5-day study period according to the MAP target.
Results were presented as hazard ratio (HR) with 95% confidence intervals (95% CI). Statistical analysis was performed using Prism Graph-Pad Software v3. 9. 1 (San Diego, California) and R (R Foundation for Statistical Computing, Vienna, Austria. URL https:// www. R-proje ct. org/) v3. 6. 2. All tests were two-sided, and p-values below 0. 05 were considered as statistically significant.
Study population Thirty-three patients were excluded because of missing data regarding mottling. Seven hundred and forty-seven patients were thus included in the analysis. Among them, 374 and 373 patients were assigned to the low-MAP target group and the high-MAP target group, respectively (Additional file 2: Fig. S1 ). Baseline characteristics and mortality at day 90 were similar in the low and high-MAP target groups (Additional file 1: Table  S1 ). MAP values measured during the first 5 days were significantly lower in the low-MAP target group than in the high-target MAP group (p < 0. 001, Additional file 2: Fig. S2 ). Patients in the high-MAP target group received higher doses of norepinephrine during the first 5 days than patients in the low-MAP target group. Fluid intake was similar in both groups (Additional file 1: Table  S2 ).
Among the 747 analyzed patients, 296 (40%) experienced mottling for at least 2 h during the first 24 h after inclusion. The median duration of mottling during the first 24 h after inclusion was 14  [1, [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]  h. Among patients with mottling, 235 (79. 4%) had mottling that lasted more than 6 h. The whole mottling monitoring (i. e. every 2 h in patients with catecholamines infusion) represented 21,544 timepoints. Data were missing at 610 timepoints (2. 8% of the entire dataset), and, after extrapolation with the LOCF procedure, only 40 timepoints data remained missing (0. 2% of the dataset). As presented in Table  1 , disease severity was higher in patients with mottling during the first 24 h than in those without mottling (higher Simplified Acute Physiology Score II (SAPS II) [63 (50-77) vs.
Our study has several limitations. First of all, the post hoc design is well known for its biases. Second, the data regarding mottling collected in the SEPSISPAM trial consisted only of the presence or absence of mottling, without information on the intensity and extent of mottling. Such information, namely the mottling score  [4] , could have been of interest in our study, to better assess whether MAP target may have an impact on mottling score intensity. However, discriminating patients with mottling from those without decreases the risk of interobserver variability and increases the robustness of mottling assessment. Third, as in the SEPSISPAM trial, achieved MAP was higher than targeted MAP, although there was still a significant difference in MAP between the low-target and high-target MAP groups.
Compounds. Compounds were obtained from ThermoFisher Scientific (amitriptyline hydrochloride, carbamazepine) and Sigma-Aldrich (chlorpromazine hydrochloride, chlorpromazine sulfoxide, clemastine fumarate salt, desloratadine, haloperidol, imipramine hydrochloride, loratadine, remdesivir, terfenadine, camostat mesylate and E64D). All compounds were solubilized in dimethyl sulfoxide (DMSO). The final concentration of DMSO was 0. 01% for all experiments. Assessment of antiviral activity. Vero-E6 cells and Calu3 cells were infected for 2 h with SARS-CoV-2 at a Multiplicity Of Infection (MOI) of 0. 2 and 0. 5 in the presence or in the absence of the tested compounds. After 48 h, SARS-CoV-2 RNA was extracted from cells or cell supernatants and quantified by RT-qPCR using Taqman technology. SARS-CoV-2 RNA relative quantities were plotted against compound concentrations and fitted with a four-parameter logistic curve with SigmaPlot v11 software.
Both models describe an autonomous ego vehicle, called car, moving around in a scene, called (geographical) map, towards a goal or destination position, and interacting with its environment, i. e. , a given set of moving obstacles (pedestrians, cyclists, other cars, etc. ) to avoid collisions. The formal models are written in the LNT language  [3, 8] , which is the most recent modeling language supported by the CADP verification toolbox  [7]  and a state-of-the-art replacement for the international standards LOTOS and E-LOTOS  [8]. We chose LNT rather than a scenario modeling language such as Scenic  [6]  to illustrate a model-based, formal verification and testing approach  [9, 16]. The first formal model specifies the control of the car (including route planning), considering an abstract representation of the geographical map as a graph.
The second model focuses on the perception components of the car, and therefore it does not need to include a specification of the vehicle's control, but requires a refined, more precise representation of the map. Both models were not yet fully disclosed. We validated both models using different approaches supported by the CADP tools. First, we checked several safety and liveness properties characterizing the correct behavior of an AV. Concretely, we expressed the properties in the MCL  [17]  data-handling, action-based temporal property language, and verified them on the models using the on-the-fly model checker of CADP. Second, we generated several relevant AD scenarios from the models. More precisely, we used TESTOR  [15] , a tool developed on top of CADP for on-the-fly conformance test case generation guided by test purposes, to generate abstract test cases, which were automatically translated into AD scenarios  [9].
Module hierarchy and scenario module The model is split in three different parts. First, a part with definitions independent of the AV, e. g. , types related to graph definitions together with the classical graph functions. Second, a generic part, defining types, functions, and processes common to all configurations. Finally, a particular part, defining the constants characterizing the considered configuration: the geographical map, the number of obstacles, as well as the initial position and behaviour of these obstacles. Stats. The resulting LNT specification has 881 lines dispatched in four modules, containing 14 types, 19 functions, six channels, and ten processes. Using CADP, for the map with 22 streets and 8 crossroads represented in Figure  2  and two obstacles, each with one random move, we generated (in about a minute on a standard laptop) the corresponding LTS (Labelled Transition System): 59,781 states and 179,884 transitions (13,305 states and 28,601 transitions after strong bisimulation minimization).
Validation by model checking We validated our LNT model by checking several safety and liveness properties characterizing the correct behavior of the AV. We expressed the properties in MCL  [17] , the data-handling, action-based, branching-time temporal logic of the on-the-fly model checker of CADP. We describe here two properties in natural language and in MCL-more were verified for the associated GRL model  [14]. Property 1: "The position of the car is correctly updated after each move of the car. " This safety property expresses that on each transition sequence, an update of the car position ("UPDATE_POSITION ?current_street", where current_street is the street on which the car currently is) followed by a car move ("CAR_MOVE ?control", where control is a move) cannot be followed by an update of the car position inconsistent with current_street, control, and the map.
To easily build various configurations of the LNT model, the scenario module enables to choose the map, the initial positions of (static and dynamic) obstacles, and the behaviour of the car. The only parameter not defined in the scenario module is the size of the map, defined in the types module because of the hierarchy. The example SCENARIO given in Appendix B contains four static obstacles and two moving obstacles (another car and a pedestrian) with a simple trajectory. We decided to place the processes RESTRAND and SCHEDULER in the scenario module because these processes depend on the number of obstacles and, for RESTRAND, on the distance from the car that is chosen for randomly moving obstacles. Stats. The resulting LNT specification has 1059 lines (excluding the scenario module, the size of which depends on the configuration-the one given in Appendix B has 161 lines) dispatched in eight modules, containing 13 types, 38 functions, seven channels, and eleven processes.
B. 4 Definitions of the geographical map Module modele_map contains all necessary functions to manage the array representing the ground truth. These functions are used to update the array and check the value of cells when moving an actor. The module also contains functions factoring some features, such as the update of an attribute or the access to an array cell. --------------------------------------------------------------------------F u n c t i o n s  --------------------------------------------------------------------------u   -------------------------------------------------------------------------u   -------------------------------------------------------------------------u   -------------------------------------------------------------------------r   -------------------------------------------------------------------------r   --------------------------------------------------------------------------r   -------------------------------------------------------------------------P r o c e s s e s  --------------------------------------------------------------------------p   -------------------------------------------------------------------------p   Besides functions to initialize the scenario, module modele_scenario contains also a process with a parallel composition with an instance of process OBSTACLE for each moving obstacle and a process instantiating the ego vehicle as a parallel composition of the motion control process MOVE_CAR and the perception process LIDAR_MANAGER.
Last, but not least, module modele_scenario contains also the processes SCHEDULER and RESTRAND, which depend on the initial position of the car and the number of moving obstacles in the scenario. --------------------------------------------------------------------------C  o n s t a n t s -  -------------------------------------------------------------------------i   -------------------------------------------------------------------------h   -------------------------------------------------------------------------F u n c t i o n  --------------------------------------------------------------------------f   -------------------------------------------------------------------------P r o c e s s e s  --------------------------------------------------------------------------p   ----------------------------------------------------------------------- --p r o c e s s h a n d l i g n t h e e g o v e h i c l e ( c a r ) b y i n s t a n t i a t i n g MOVE CAR --w i t h a p p r o p r i a t e v a l u e s   -------------------------------------------------------------------------p   -------------------------------------------------------------------------p   ----------------------------------------------------------------------- end module Different scenarios are obtained by simply modifying the contents of module modele_scenario.
B. 7 Definitions for the environment of the autonomous vehicle Module modele_map_manager contains the process managing the ground truth map. Observing the moves of the actors (car and obstacles), process MAP_MANAGER updates the map accordingly. It also detects and signals a collision of the car with an obstacle. Module modele_map_manager also contains the process ENVIRONMENT, which models the environment of the autonomous vehicle, i. e. , the parallel composition of the moving obstacles and the map manager. -------------------------------------------------------------------------p   ----------------------------------------------------------------------- end module.
(b 1 and b 2 ) were measured as surrogates of aortic root endothelial permeability and compared with macrophage density by immunohistochemistry. b 2 , indicating contrast agent washout, was significantly higher in mice kept on an high-fat diet for longer periods of time (p = 0. 03). Group comparison revealed significant differences between mice on a high-fat diet for 4 versus 16 weeks (p = 0. 03). Macrophage density also significantly increased with diet duration (p = 0. 009). Spearman correlation between b 2 from DCE-MRI and macrophage density indicated a weak relationship between the two parameters (r = 0. 28, p = 0. 20). Validated piecewise linear modeling of the DCE-MRI data showed that the aortic root contrast agent washout rate is significantly different during disease progression. Further development of this technique from a single-slice to a 3D acquisition may enable better investigation of the relationship between in vivo imaging of endothelial permeability and atherosclerotic plaques' genetic, molecular, and cellular makeup in this important model of disease.
| Self-gated DCE-MRI: Reconstruction First navigator signals from the whole acquisition were automatically treated on the scanner for rejection of respiratory events, resulting in approximately 30% of the total k-space data being eliminated from further processing. Further processing was performed using custom-made local maximum detection algorithm was then applied to the navigator signal in each temporal frame to identify the start of each cardiac cycle. All detected cardiac cycles were divided into six heart phases. k-lines acquired within a specific temporal frame were then assigned to these previously determined heart phases depending on their acquisition time within each cardiac cycle. Taking into consideration the approximately 30% of discarded k-space lines to account for respiratory motion, this resulted in 4.