dataesr/scientific-paragraphs-categorization huggingface dataset:
Statistical Analysis Each condition was repeated three to five times, depending on the experiment. For purification methods, the experiment were performed five times. The results were expressed as means with standard deviations (±SD). For the quantification of the metabolites, the analyses were repeated three times, and the data were expressed as mean ± SD, p < 0. 001. For statistical analysis, Excel 2013 (Microsoft Office) and SPSS statistics 20 (IBM) were used. For PCA, SIMCA software version 16. 0. 2 (Umetrics, Umeå, Sweden) was used, and the PCA was realized using the Pareto scaling method.
Principal Components Analysis (PCA) Comparison of the dynamics of the accumulation of both flavonol glycosides and terpene trilactones from the closed-bud stage to the summer leaf stage revealed similar profiles for both types of components. However, the accumulated quantities were greater for flavonoid glycosides than for terpene trilactones, regardless of the physiological stage of development. To identify groups of similar individuals in a dataset, principal components analysis (PCA) was chosen (Figure  6 ). The PCA score plot revealed that the first and second principal axes accounted for 93. 3% and 3. 5% of the total variability, respectively. The score plot represents the proximity between the samples. The PCA ordination clearly discriminated buds and leaves. In addition, a weak variability between the three replicates of the leaves is visible.
Introduction Reversible cerebral vasoconstriction syndrome (RCVS) is characterised by severe acute headache associated with segmental cerebral vasoconstriction resolving within 3 months  [1, 2]. It predominantly affects women in their forties or fifties, with an age range of 4 months to 85 years  [3] [4] [5]. Clinical spectrum of RCVS is heterogeneous ranging from pure cephalalgic forms to complications including focal deficits, seizures, ischaemic stroke, intracranial haemorrhage, posterior reversible encephalopathy syndrome and cervical artery dissection  [6] [7] [8] [9] [10] [11] [12] [13] [14]. Potential risk factors for such complications include female sex, postpartum, the absence of thunderclap headache at onset, and use of serotonergic antidepressants  [8] [9] [10] 15]. Recently, analyses of the US Nationwide Readmission and Inpatient Databases identified advanced age as an independent risk factor for intracranial haemorrhage during RCVS, for higher length-of-stay in hospital, and for poor early outcome defined by discharge from hospital other-than-home  [6, 16].
Further clinical follow-up visits were performed as previously described, with a mean follow-up period of 9. 2 ± 3. 3 years  [17]. After the end of the prospective study at Lariboisière Hospital, patients were retrospectively included from 2012 to 2015, following the same inclusion criteria (cohort B, n = 132). 80% of the patients were recruited from the EHC, and 20% from the neurology department. At the University Hospital of Montpellier, patients were retrospectively identified from the electronic database by using the International Classification of Diseases codes I67. 84 and I67. 9 from 2016 to 2019. For all identified cases (cohort C, n = 40), we analysed their medical records to ensure that they met the above-mentioned inclusion criteria. All identified patients had been admitted to the neurology department.
For both retrospective cohorts, clinical routine included a follow-up appointment at 3 months in order to clinically and radiologically confirm the diagnosis of RCVS according to the above-mentioned criteria, and to assess functional outcome. Ethics approvals were obtained from the respective local institutional review boards. The database used in the study was approved by the Commission Nationale Informatique et Liberté. The study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments.
Definitions of clinical characteristics Migraine was diagnosed according to the International Classification of Headache Disorders  [18]. A thunderclap headache (TCH) was defined as a headache reaching a maximum intensity above 7/10, on an 11-point scale from 0 to 10 in < 1 min. We assessed the delay between onset, precisely the first episode of headache or neurological deficit, and the first neurological examination. RCVS was qualified as secondary in the presence of a potential precipitating factor and as idiopathic when none could be identified. We collected data on the occurrence of clinical symptoms (i. e. , transient focal neurological deficit < 24 h, persistent focal neurological deficit ≥ 24 h, and seizure) and of radiological lesions (i. e. , ischaemic stroke [IS], intracerebral haemorrhage [ICH], subarachnoid haemorrhage [SAH], subdural haematoma [SDH], posterior reversible encephalopathy syndrome [PRES], and cervical artery dissections [CAD]), defined as complications of RCVS.
With respect to brain lesions, subarachnoid haemorrhage was the most common complication in the entire cohort, followed by intracerebral haemorrhage. This finding is in line with the results of the above-cited observational study from the 2016 US Nationwide Readmission Database, reporting haemorrhagic complications in 43% of patients  [16]. The authors identified female sex as well as middle to older agegroup as independent risk factors for a combined outcome of ICH, SAH and SDH. Topcuoglu et al. compared haemorrhagic and nonhaemorrhagic RCVS, and found that female sex but not age was a predictor for intracerebral haemorrhage  [28]. A former analysis of the first 89 patients from our cohort identified female sex and migraine as risk factors for haemorrhagic manifestations of RCVS  [29]. In the present study, the number of cases allowed for separate analysis of ICH and SAH, revealing an independent association of increasing age with ICH as well as SAH.
Population-based studies have associated age-dependent vascular stiffness and risk of cardiovascular events including IS in the elderly, and one study identified increased arterial stiffness as a predictor of delayed IS in patients with SAH  [32, 33]. Among patients with RCVS, an analysis of the US Nationwide Readmissions Database 2016-2017 found a higher risk for IS in patients with hypertension, diabetes and tobacco use, but no association with age  [34]. Likewise, in our cohort, age was not associated with IS, but the number of IS was low and larger studies are required. CAD showed a non-linear association with age, peaking at 30-39 years. To date, the causal and chronological relation between CAD and RCVS remains unclear and has been the subject of previous publications  [35] [36] [37].
Larger studies with cluster analyses, such as conducted in transient global amnesia  [45] , a condition sharing numerous features with RCVS, are necessary to statistically confirm the existence of such subgroups. The overall clinical outcome at 3 months of follow-up in our cohort was very good with an mRS score 0-1 in 96. 5% of patients. Contrarily, an analysis of the US Nationwide Inpatient Database including 2020 patients with RCVS found a poor early outcome of discharge to another facility after hospitalisation or in-hospital death in one third of patients  [6]. This discrepancy might be explained mainly by different recruitment patterns. While the US study described a population of hospitalised patients, two third of our patients were recruited from an emergency headache center, and one third of our patients were treated on an outpatient basis  [9].
Abstract The rapid evolution of SARS-CoV-2 to variants with improved transmission efficiency and reduced sensitivity to vaccine-induced humoral immunity has abolished the protective effect of licensed therapeutic human monoclonal antibodies (mAbs). To fill this unmet medical need and protect vulnerable patient populations, we isolated the P4J15 mAb from a previously infected, vaccinated donor, with <20 ng/ml neutralizing activity against all Omicron variants including the latest XBB. 2. 3 and EG. 1 sub-lineages. Structural studies of P4J15 in complex with Omicron XBB. 1 Spike show that the P4J15 epitope shares ~93% of its buried surface area with the ACE2 contact region, consistent with an ACE2 mimetic antibody. Although SARS-CoV-2 mutants escaping neutralization by P4J15 were selected in vitro, these displayed lower infectivity, poor binding to ACE2, and the corresponding 'escape' mutations are accordingly rare in public sequence databases.
Structural studies reveal that this broad activity can be attributed to the high binding surface area of the P4J15 epitope, which includes residues essential for efficient ACE2 binding and infection. Live virus resistance studies confirmed that P4J15 escape mutants selected in cell culture were poorly infectious, owing to RBD mutations strongly reducing affinity for the ACE2 receptor. Accordingly, the corresponding escape mutations were found only at low frequency in the GISAID sequence database, confirming their detrimental effect on virus fitness. Finally, P4J15 conferred near complete protection from infection in hamster and monkey live virus challenge studies performed with Omicron BA. 5 and XBB. 1. 5 variants, respectively. With this demonstrated in vivo efficacy against the most recent variants, neutralizing potency and breadth of protection, we propose that P4J15 could be a strong candidate for clinical development.
P4J15 is a potent and broadly neutralizing anti-SARS-CoV-2 monoclonal antibody As part of a longitudinal study to monitor the waning humoral immune response in a cohort of 20 donors, we performed routine serum testing of anti-Spike and anti-Nucleocapsid antibodies. 1a-b ). Profiling studies in a Luminex Spike binding assay showed that the purified P4J15 mAbs bound SARS-CoV-2 Spike proteins in our panel with IC50 values ranging from 0. 6 to 1. 5 ng/ml (Supplementary Data Fig. 1b ) and RaTG13 Spike with an IC50 of 11 ng/ml. Using our Spike-ACE2 surrogate neutralization assay, we also found that P4J15 had the most potent and broadest activity in blocking ACE2-binding to Spike trimers from our extensive panel of SARS-CoV-2 variants, with IC50 values below 5 ng/ml (Supplementary Data Fig. 2a-b ).
However, the infectivity of select VLPs was reduced with Spike proteins harboring many of the escapee mutations (Fig. 3d ) including A475D and N487D in the BA. 2. 75. 2 Spike and N487D, N487K and N487T in BQ. 1 Spike. Furthermore, using the ACE2-RBD interactive tool developed by Jesse Bloom's lab  (20) , it was found that all the Spike escape mutations in RBD induced a strong, 1-to 3-log reduction in binding affinity for ACE2 relative to the Omicron BA. 2 Spike reference strain (Fig. 3e ). The reduced binding affinity of ACE2 for the Spike RBD escape mutations was expected based on our structural data in Figure  2e-g , as these residues are important for both P4J15 and ACE2 binding to the RBD. Furthermore, we examined the GISAID EpiCoV database to determine the frequency of the Spike mutations mediating escape to P4J15 neutralization.
Although epistasis is always possible to complement for deleterious mutations  (24) , the almost complete absence of these specific resistance mutations within the GISAID database confirms that the virus cannot easily escape the type of inhibition imposed by P4J15 without compromising its ability to spread in the population. Of note, substitutions at some of the incriminated positions are detectable in public sequence databases, albeit at very low frequency, but these mutations do not confer resistance to neutralization by P4J15, which requires very specific amino acid substitutions. Finally, in vivo efficacy studies performed with two animal models demonstrate that P4J15 provides exceptional levels of protection against infection. In hamsters challenged with the Omicron BA. 5 virus, animals pre-dosed with 0.
As a result of these factors, the most vulnerable in our population, the immunocompromised, those with comorbidities such as cancer and the elderly, who are unable to mount a strong protective humoral immune response after vaccination  (31) , are at significantly increased risk of hospitalization and death. Given the potent neutralizing activity of P4J15, its ACE2 mimetic properties that may help to limit the development of resistant virus and the impressive complete in vivo protection in the non-human primate model, this monoclonal antibody has the potential to be a superior anti-SARS-CoV-2 mAb for prophylactic and/or potentially therapeutic interventions. Furthermore, the breath of potent neutralizing activity against all current VOCs and variant quasi-species within public SARS-CoV-2 sequence databases suggests that it may be able to neutralize many future VOCs that could emerge in the months and years ahead, providing a sustainable and long-lasting solution to protect the most vulnerable in our population.
Cryo-electron microscopy model building To generate initial models of the P4J15 Fab and XBB1 spike, various approaches were employed. These included utilizing models from the Spike trimer (PDB ID 7QO7), AlphaFold2 (implemented through ColabFold), and ModelAngelo 0. 3  (43)  for sequence-based generation. The cryo-EM maps were fitted with the Spike trimer using UCSF ChimeraX, serving as the starting point for further manual refinement. Manual extension and building of the docked models were carried out using Coot 0. 9. 8  (44). To refine the models, Phenix 1. 20  (45)  was employed. The generated figures depicting the models were prepared using UCSF ChimeraX. The numbering scheme for the full-length Spike models within the global map is based on Omicron numbering. For models containing only the RBD within the local maps, wild-type numbering is utilized.
Elodie Guyon ,  Julien Dinh  and  Eloise Joffroy  for the NHP sample processing;  Sylvie Legendre  for the transport organization;  Frédéric Ducancel ,  Alicia Pouget  and  Yann Gorin  for the logistics and safety management;  Isabelle Mangeot  and  Salome Piault  for help with resources management and  Brice Targat  and  Karl-Stefan Baczowski  who contributed to data management. The virus stock used for the NHPs was obtained from the  Biodefense, Research Resources , and  Translational Research  branches of the  NIH/NIAID/DMID /OBRRTR/RRS (Program Officer, Clint Florence, Ph. D. ). The  Infectious Disease Models and Innovative Therapies research infrastructure  (IDMIT) is supported by the " Programme Investissements d'Avenir"   (PIA) , managed by the  ANR  under references  ANR-11-INBS-0008  and  ANR-10-EQPX-02-01.
We would also like to thank  Trudi Veldman  and members of the  CARE-IMI  work package 4 team for helpful discussions. G. P. and R. L. received a grant from the  Corona Accelerated R&D in Europe (CARE)  project funded by the  Innovative Medicines Initiative 2 Joint Undertaking (JU)  under grant agreement No  101005077. The JU receives support from the  European Union 's  Horizon 2020 research and innovation program , the  European Federation of Pharmaceutical Industries Associations (EFPIA) , the  Bill & Melinda Gates Foundation ,  Global Health Drug Discovery Institute  and the  University of Dundee. The content of this publication only reflects the author's view and the JU is not responsible for any use that may be made of the information it contains. G. P. and D. T. received support from the  CoVICIS  project (grant No.
10146041 ) funded by the  European Union Horizon Europe Program. Additional funding was provided through the  Lausanne University Hospital  (to G. P. ), the  Swiss Vaccine Research Institute  (to G. P. and  NCCR TransCure  to H. S. ),  Swiss National Science Foundation Grants  (to G. P. ) and through the  EPFL COVID fund  (to D. T. ) and a donation from a private foundation advised by  CARIGEST S. A. (to DT and GP).
). All other aspects with cell sorting, immortalization protocol using EBV positive supernatants form B95-8 cells and cloning were as described in Fenwick et al (17). Sequences for mAbs P4J15 are provided in PDB submissions PDB-8PQ2 and EMD-17819. SARS-CoV-2 live virus stocks All biosafety level 3 procedures were approved by the Swiss Federal Office of Public Health. The SARS-CoV-2 BA. 2. 75. 2 (EPI_ISL_14795784) and BQ. 1 (EPI_ISL_15369810) isolates were a kind gift from I. Eckerle, Geneva University Hospitals. Viral stocks were prepared in EpiSerf (ThermoFisher Scientific, USA) with a single passage on VeroE6 cells, aliquoted, frozen, titrated on VeroE6 cells by conventional plaque forming units and sequence verified. BA. 2. 75. 2 isolate differed from our cloned BA. 2. 75. 2 ORF by 1 supplemental mutation (G181V) already found in the original virus isolated from the patient.
Patients and studies The methodology and study details of the studies included in this pooled analysis have been previously reported  [4]. Briefly, eight randomized, placebo-controlled phase 2b/3 studies (NCT00199394, NCT00199407, NCT00199420, NCT00455507, NCT00456586, NCT00456794, NCT00955526, NCT01968031) were conducted in North America, Japan, or internationally. These studies enrolled patients with PD experiencing motor fluctuations (end-of-dose wearingoff) during treatment with LD/decarboxylase inhibitors, with or without other anti-PD medications. Patients were randomized to receive istradefylline or placebo; while the studies included several doses of istradefylline  (10, 20, 40 , or 60 mg/day), only the 20 and 40 mg treatment arms were selected for inclusion in the pooled analysis, as the 20 and 40 mg doses are approved for use in clinical practice and were used by the majority of the patients in the eight randomized studies  [7].
Funding This study was funded by Kyowa Kirin, Inc. Not included: Patients with mixed subtype (n = 188) and patients not evaluable on the basis of TD and/or PIGD scores (n = 248). COMT, catechol-O-methyl transferase; DA, dopamine agonist; LD, levodopa; MAO-B, monoamine oxidase type B; PIGD, postural instability and gait difficulty; SD, standard deviation; TD, tremor dominant. a For studies in which the primary endpoint (OFF time) was recorded as the percentage of awake time (eg, % OFF), data were converted to hours/day for pooling. b Data not collected in all eight studies.
Acknowledgments The authors thank  Meghan Sullivan, PhD , and  Anthony DiLauro, PhD , of  MedVal Scientific Information Services, LLC , for medical writing and editorial assistance, which were funded by  Kyowa Kirin, Inc. This study was funded by  Kyowa Kirin, Inc. This manuscript was prepared according to the International Society for Medical Publication Professionals' "Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3. ".
Statistical Analysis The association between the incidence of colic and the presence of various infectious agents (betacoronaviruses, endoparasites, and bacteria) was evaluated via Fisher's exact tests (FET) for count data in R (R version 4. 1. 2, function fisher. test)  [49]. The reported odds ratios are translated as the ratio between the odds of colic occurrence in the presence and absence of the infectious agent, respectively. The resulting p-values were adjusted for multiple testing according to Benjamini and Hochberg's false discovery rate (FDR) correction  [50]. Significance was declared at an FDR cut-off of 5%.
The sequences obtained from the three remaining betacoronavirus 1-positive samples were clustered with bovine coronaviruses (Table  2 ). A phylogenetic tree showing N gene sequences of equine and bovine coronaviruses is shown in Figure  1. The obtained sequences are registered in GenBank with the accession numbers: OP554362  (  Among the horses in the colic group, six individuals tested positive for ECoV or BCoV. These horses exhibited mild to moderate colic signs and did not display a body temperature exceeding 38 • C during their initial clinical examination. Two of these horses had decreased fecal consistency. One patient showed lethargy and two presented with mild to moderately decreased body condition, including one showing both clinical signs. Four of these horses showed an impaction of the ascending colon.
Parasitological Findings-Fecal Parasitology and Molecular Investigation Strongyle eggs were detected in 53 of the 141 samples (low to high grade, 3 (Table  3 ) and showed a significant negative association with colic occurrence (FET ratio = 0. 29, FDR = 0. 025). Considering the coronavirus-infected horses, only one E positive horse showed a low intensity of strongyle egg shedding. Other sequences were downloaded from GenBank. Maximum Likelihood method and Tamura-Nei model  [43]  evolutionary analyses were conducted in MEGA11.
Pathogens 2022 ,Figure 1. 20221 Figure 1. Phylogenetic analysis of complete N gene nucleotide sequences (ECoV: 1341 nucle BCoV: 1347 nucleotides). Numbers next to the nodes represent the bootstrap values; only boo values > 70% are shown (1000 replicates). The scale bar represents a length corresponding nucleotide substitutions per site. Sequences obtained in this study are marked with a blac Other sequences were downloaded from GenBank. Maximum Likelihood method and Tamu model [43] evolutionary analyses were conducted in MEGA11.
Perhaps a multifractal testing combining entropy concepts/calculations may help to capture subtle differences in HRV during cognitive tasks. Here, it is hypothesized that multifractal testing of HRV using the method of Chhabra and Jensen may provide reliable estimators to complete the picture of cardiovascular complexity. To validate this hypothesis, multifractal testing based on Shannon entropy was used for a reanalysis of HRV measures obtained during cognitive tasks. Some links between task and specific HRV metrics have already been shown by applying multiscale sample entropy and multiscale-multifractal DFA to the same dataset so that new information is expected here.
Discussion Multifractal testing has been the subject of intense research in recent years to describe the complexity of control systems, including posture  [12] , cognition  [10, 26, 27] , movement  [19, 20, 28] , and cardiovascular control  [17, 18]. The present study, elaborating on a dataset obtained during cognitive tasking, aimed at exploring multifractal estimates of HRV complexity derived from a direct determination of the multifractal spectrum based on Shannon entropy metrics: the Chhabra and Jensen method  [14]. Exploring new estimates is based on the intuition that different aspects of complexity can be reflected by specific markers, which depends on how entropy-based or fractal-based metrics are computed, as illustrated in recent studies  [2, 13]. Specifically, different components of the multifractal spectrum reflecting large-sized and small-sized fluctuations in HRV were evaluated here (a).
Discussion Multifractal testing has been the subject of intense research in recent years to describe the complexity of control systems, including posture  [12] , cognition  [10, 26, 27] , movement  [19, 20, 28] , and cardiovascular control  [17, 18]. The present study, elaborating on a dataset obtained during cognitive tasking, aimed at exploring multifractal estimates of HRV complexity derived from a direct determination of the multifractal spectrum based on Shannon entropy metrics: the Chhabra and Jensen method  [14]. Exploring new estimates is based on the intuition that different aspects of complexity can be reflected by specific markers, which depends on how entropy-based or fractal-based metrics are computed, as illustrated in recent studies  [2, 13]. Specifically, different components of the multifractal spectrum reflecting large-sized and small-sized fluctuations in HRV were evaluated here and confronted with cardiovascular responses to four different cognitive challenges that rely on distinctive cognitive-autonomic interplay (Figure  2 ).