dataesr/scientific-paragraphs-categorization huggingface dataset:
• White-box attacks: The defense technique is effective for almost all the classifiers against the FGSM, PGD and BIM. As for JSMA, the robustness is also improved for all classifiers, and Gradient Boosting has the best performance. The behavior of the classifiers is similar in both databases. 5. 2. 2. 2. False negative rate. The results are shown in the fourth sub- table, and will be compared with the second sub-tables, where the FNR is measured without defense technique.
Introduction 2-(2'-Hydroxyphenyl)benzoxazole (HBO) derivatives are wellknown versatile organic fluorophores whose facile synthesis enables the investigation of the impact of incremental structural inputs on their photophysical properties. 3] [4]  ESIPT is a phototautomerization reaction which turns, in most cases, an excited enol (E*) derivative into the corresponding keto (K*) upon proton migration and structural reorganization. The radiative relaxation of this excited keto species to the ground-state leads to a strongly red-shifted fluorescence emission (Figure  1 ). [5] [8] [9]  As a result, a rich database of optimized ESIPT dyes has been engineered and applied to numerous applications, including optoelectronic devices,  [10] [11]  bio-sensing or -imaging,  [12] [13]  security inks,  [14]  white luminescence  [15] [16] [17]  along with various luminescent displays.
The photophysical properties in solution (toluene, ethanol) and in the solid-state (KBr pellet), of all synthesized dyes, along with the data for the unsubstituted HBO used as benchmark are listed in Table  S2   3b ). The first band, intense and structured is found below 320 nm and can be ascribed to the π!π* transitions of the benzoxazole units (Table  S2 ). The second band, rather broad and unstructured, located between 326 and 332 nm in toluene and 319 and 333 nm in ethanol can be attributed to the S 0 !S 1 transition characteristic of the HBO dye. [23] [24]  HBO-3,5-(tolyl) 2 dye stands out in the series with a recorded bathochromic shift of the maximum absorption wavelength (λ abs = 352-354 nm), highlighting a stronger electronic connection between the tolyl unit and the HBO core, which is also found in the simulations (vide infra).
These data are in alignment with the emission of unsubstituted HBO (λ em = 499 nm), consistent with the absence of rotation owing to the presence of mesityl or tip substitution at the 3, 5 or 3,5 position of the phenol. These data are also consistent with theoretical simulations (vide infra). In ethanol, a dual E*/K* profile is observed in all cases with the notable exception of HBO-3,5-(Mes) 2. Moreover, for HBO-3-Mes and HBO-3,5-Tip, an additional third band is observed, located between E* and K* leading to a triple emission (Figure  3b ). Based on previous reported studies on the photophysics of related HBO derivatives, this band can be unambiguously ascribed to the deprotonated species D*, originating from a competitive deprotonation process in the excited state. [22, 27, 33] ll calculated photoluminescent calculated quantum yields (PLQY) lie within the same range as the HBO reference, i.
A notable difference between the optical properties observed in toluene and those recorded in ethanol is the A*/K* intensity ratio; the K* and A* being the most intense bands in toluene and ethanol, respectively. A tentative explanation resides in the difference of viscosity between the two solvents (0. 53 and 0. 97 mPa-s for toluene and ethanol, respectively). [34] The enhanced viscosity of ethanol leads to a stabilization of the A* species. The photophysical data determined for HBO-5-Ant are in line with a reported benzimidazole analogue, where the authors evidence a rotation in the excited state of the anthracene sub-unit to yield a quasi-planar conformation. [35] ll dyes described herein display intense emission as amorphous powders under irradiation with a UV-lamp (λ exc = 365 nm) (Figure  5b ).
02 mmol. ) were added under argon. The resulting mixture was stirred overnight at 90 °C using an oil bath, before the solution was quenched with 2 M HCl, extracted with ethyl acetate, washed with brine, dried over MgSO 4 and concentrated under vacuum. The crude residue was first filtered on silica gel eluting with CH 2 Cl 2 , before it was solubilized in 10 mL of dry CH 2 Cl 2 , and a 1 M solution of BBr 3 in CH 2 Cl 2 (1 mmol. ) was added dropwise at 0 °C. The resulting mixture was allowed to stir at room temperature for 15 hours. The reaction was quenched with methanol over 2 hours and concentrated under vacuum. The crude residue was purified by silica gel chromatography. nary Institute HiFunMat, as part of the ITI 2021-2028 program of the University of Strasbourg, CNRS and Inserm, was supported by IdEx Unistra (ANR-10-IDEX-0002) and SFRI (STRA-T'US project, ANR-20-SFRI-0012) under the framework of the French Investments for the Future Program.
Acknowledgments The authors thank the  ANR  for support in the framework of the  GeDeMi grant  ( PhD fellowship  for T. P. ). A. D. L. and D. J. thank the  CCIPL (Centre de Calcul Intensif des Pays de la Loire ) for the always generous allocation of computational time. T. S. acknowledges the ministère de l'enseignement supérieur et de la recherche for a PhD fellowship. This work of the Interdiscipli-.
nary Institute HiFunMat, as part of the ITI 2021-2028 program of the University of Strasbourg, CNRS and Inserm, was supported by IdEx Unistra (ANR-10-IDEX-0002) and SFRI (STRA-T'US project, ANR-20-SFRI-0012) under the framework of the French Investments for the Future Program. CuI (0. 55 mmol) was then added and the mixture stirred for another 30 min. Then, a solution of Pd(OAc) 2 (0. 025 mmol), tris(ometh-oxyphenyl)phosphine (0. 075 mmol) and 2-bromomesitylene or 2-bromoanthracene (0. 55 mmol) in THF (15 mL) was added via a cannula, keeping the temperature at 0 Suzuki-Miyaura cross-coupling reaction conditions on 3,5-dihalo-genosalicylaldehyde: In a Schlenk tube, 3,5-dihalogenosalicylalde-hyde (1 mmol. ), 2,4,6-trimethylphenyl boronic acid (3 mmol. ), base (3 mmol. ) were dissolved in solvent (45 mL/mmol.
Antivector antibodies were observed at baseline in a subset of individuals and expanded by GRAd-COV2 vaccination GRAd neutralization was not set as a screening or a randomization parameter but was assessed as an exploratory end point at baseline and 4 weeks after vaccination. Of 90 volunteers, we measured neutralization titers of >200, a value above which an impact on vaccine immunogenicity has been reported, in only 10 volunteers (11%). As expected, vaccination with GRAd-COV2 induced or boosted antivector immunity in most volunteers (Fig. 5A ), with no differences attributable to vaccine dose or age. To assess the impact of anti-GRAd immunity, pooled immunogenicity data at peak after vaccination (T cell responses or binding and neutralizing antibody responses) were stratified according to the baseline GRAd-neutralizing titers (Fig.
It will be important therefore to extend GRAd seroprevalence studies to world regions outside Europe or the United States that are more likely to benefit from adenovirus-based COVID vaccines in the near future. Our interim analysis indicates that vaccine candidate GRAd-COV2 is safe and immunogenic in both younger and older adults. This finding has supported and guided our decision to proceed with an ongoing phase 2/3 trial (NCT04791423) to evaluate the efficacy of either a single-dose or of a two-dose regimen of GRAd-COV2. Experience from other ongoing clinical trials on adenovirus-based vaccines provided evidence that a second administration of vaccine is safe and can improve the production of SARS-CoV-2 neutralizing antibodies  (12, 13). The observed increase of anti-GRAd neutralizing antibody titers after vaccination is in line with that observed with other adenovirus-based COVID-19 vaccines (9, 10), which did not prevent boosting of anti-spike protein antibodies upon a second administration.
The volunteers received a single intramuscular injection in the deltoid. For administration of the high dose, 1 ml of GRAd-COV2 was injected without dilution. For low-dose and intermediate-dose arms, the vaccine was diluted in sterile saline solution to reach a final 1-ml injection volume. Volunteers were expected to attend several visits, at day 2 and weeks 1, 2, 4, 8, 12, and 24 after vaccination. During the visit, the volunteers underwent blood sampling and medical evaluation. Participants also discussed with a doctor any potential AEs. The dose-escalation staggered enrollment included three sentinel volunteers in the low-dose arm followed by enrollment of the full low-dose arm. Intermediate-and high-dose sentinel volunteers were enrolled 7 days after that safety data of low-dose or intermediatedose arms were available, respectively.
Ethical statement All participants provided written informed consent before enrollment. The trial was conducted at the National Institute for Infectious Diseases Lazzaro Spallanzani (INMI) in Rome and at Centro Ricerche Cliniche in Verona. The study was conducted according to the Declaration of Helsinki and was approved by the Italian Regulatory Drug Agency (AIFA) and the Italian National Ethical Committee for COVID-19 clinical studies (ClinicalTrials. gov, NCT04528641; European Union Drug Regulating Authorities Clinical Trials Database, 2020-002835-31). Serum samples from convalescent patients who resolved SARS-CoV-2 infections came from residual specimens used for diagnostic purposes and were used according to INMI protocols for observational studies approved form internal ethical committee.
SARS-CoV-2 MNA Serum samples collected from vaccinated volunteers or convalescent patients with COVID-19 were heat-inactivated at 56°C for 30 min and titrated in duplicate in seven twofold serial dilutions (starting dilution of 1:10). Equal volumes of 100 TCID 50 (median tissue culture infectious dose) of SARS-CoV-2 (strain 2019-nCoV/ Italy-INMI1; GISAID accession ID: EPI_ISL_412974) and serum dilutions were mixed and incubated at 37°C 5% CO 2 for 30 min. Subsequently, 96-well tissue culture plates with subconfluent VeroE6 cell [American Type Culture Collection (ATCC)] monolayers were infected with 100 l per well of virus-serum mixtures and incubated at 37°C and 5% CO 2. To standardize interassay procedures, positive control samples showing high (1:160) and low (1:40) neutralizing activity were included in each MNA assay.
5% bovine serum albumin (Sigma-Aldrich), 0. 01% sodium azide (SERVA Serving Scientists), and 0. 5% saponin (Sigma-Aldrich) for 30 min at room temperature. Acquisition of 200,000 events was performed in the CD3 + gated population on a CytoFLEX LX flow cytometer and analyzed with CytExpert software (Beckman Coulter). Data were analyzed with CytExpert software [Beckman Coulter; doublets were excluded in the forward scatter height (FSC-H)/forward scatter area (FSC-A) dot plot]. Live cells were selected as ViaKrome-negative cells. Next, CD45 + were gated, followed by gating of CD3 + lymphocytes. Among the CD3 + cells, CD4 + or CD8 + cells were selected, and the percentage of CD4 or CD8 T cells producing cytokines was Downloaded from https://www. science. org at Universite Pierre Et Marie Curie -Paris 6 (Upmc) on January 19, 2022 evaluated.
Statistical analysis Categorical variables, including occurrence of AEs and detection of binding and neutralizing antibodies against SARS-CoV-2 and GRAd, were reported as proportions. Continuous variables, including results of CLIA anti-spike protein IgG, MNA 90 titers, PNRT 50 titers, and ELISpot values for IFN- secretion, were reported as the median and interquartile range. Comparison of medians across arms and the impact of preexisting immunity against GRAd were evaluated by a two-tailed Kruskal-Wallis one-way variance analysis. Associations between categorical variables were carried out using Fisher's exact test. Correlations between immunogenicity assays were assessed by nonparametric Spearman's rank tests. Data in Fig. 6  were analyzed by Friedman's test with Dunn's multiple comparisons correction.
reciprocal of serum dilution (MNA 90 ). Serum from the NIBSC with known neutralization titer was used as a reference in MNA (NIBSC, code 20/130). Where indicated, two alternative viral strains were used to test serum sample neutralizing activity against SARS-CoV-2 VOCs (hCoV-19/Italy/LAZ-INMI-129/2020 lineage B. 1. 1. 7, GISAID accession ID: EPI_ISL_765567 and hCoV-19/Italy/LAZ-INMI-216isl/2021 lineage P. 1, GISAID accession ID: EPI_ISL_1023524).
Methods We have set-up a unified library of Bordetella genomes by merging previously existing Oxford and Pasteur databases, importing genomes from public repositories, and developing harmonized genotyping schemes. We developed a genus-wide cgMLST genotyping scheme and incorporated a previous B. pertussis cgMLST scheme. Specific schemes were developed to define antigenic, virulence and macrolide resistance profiles. Genomic sequencing of 83 French B. bronchiseptica isolates and of B. tumulicola, B. muralis and B. tumbae type strains was performed.
Some Bordetella species have been found in environmental samples, such as B. petrii or the three recently described species B. muralis, B. tumulicola and B. tumbae  [18] [19] [20]. In addition to these 16 current Bordetella species with standing in the prokaryotic taxonomy, additional Bordetella genogroups (as also named Bordetella genomospecies in INSDC bioproject PRJNA385118) were identified from patients with cystic fibrosis and may represent additional separate Bordetella species  [21]. The diversity of lifestyles and medical importance of Bordetellae raise important questions about the origins and evolution of pathogenicity in this group  [4]. Horizontal gene transfer (HGT) is likely to occur between Bordetella species and strains, as already observed for the O-antigen locus in B. bronchiseptica  [22].
For example, the environmental species B. petrii has genomic islands with atypical G+C content  [18]  that were associated with the metabolic versatility of this species. The use of a unified database of genomes from all Bordetellae species would facilitate genomic analyses underlying the phenotypic diversity within this important bacterial genus. Besides the large-scale evolution of Bordetellae, the population dynamics within Bp are an important topic of epidemiological surveillance, in light of vaccine-escape evolution and the possible emergence and global dissemination of antimicrobial resistance  [23] [24] [25]. Major evolutionary events in vaccine antigen-related genomic features have been described, including within the promoter region of the pertussis toxin gene cluster (ptxP) and in the fimbriae gene fim3  [23].
Bioinformatics platforms that centralize allele definitions and allow curation and open access to genotype nomenclature are critical resources for unified pathogen subtype definitions  [28]. Until now, there have been two dedicated Bordetella genome sequence databases: Oxford University's PubMLST (unpublished) and Institut Pasteur's BIGSdb  [29]  platforms. This duality has led to nomenclatural confusion and suboptimal services to the user's community. With the rapid developments of genomic epidemiology and biodiversity surveys, a common and optimized resource for Bordetella evolutionary studies and sequence variants naming is needed. Here, we aimed to set-up such a unified genomic platform and expand its features to enable addressing genus-wide evolutionary genomics questions and global tracking of important genotypes within individual species, and particularly B.
Development of pan-genus Bordetella cgMLST scheme A genus-wide core genome MLST scheme  [35] , called Bordetella cgMLST v1. 0, was established alongside a genus-wide locus annotation system (BORD loci), using the principles published for the genus Neisseria  [36]. Six finished and annotated Bordetella genomes were uploaded into the BIGSdb Oxford database  [37] : Bordetella pertussis Tohama I  [38] ; Bordetella pertussis CS  [39] ; Bordetella bronchiseptica RB50  [38] ; Bordetella parapertussis 12822  [38] ; Bordetella petri 12804  [18] ; and, Bordetella avium 197N  [40]. Using the GenomeComparator module of BIGSdb, the greatest number of common genes (1469) was found when B. bronchiseptica RB50 was used as the reference genome (even though B. petri 12804 had the greatest number of annotated loci, 5023).
Genes described as 'hypothetical' or 'putative' were removed, resulting in 1415 loci. All loci entered into the database were given a BORD number of the format BORD000000, where the last six digits corresponded to the BB0000 numbers used in the annotation of B. bronchiseptica RB50  [38]. Other annotations and known aliases were included in the locus descriptions for comparison. As with other genus-wide locus schemes, this scheme can be expanded simply by adding additional loci, to give an expandable catalogue of the genus pangenome.
Merging of the Oxford and Pasteur databases Two BIGSdb databases were originally designed separately for distinct purposes: while Oxford's PubMLST database offered MLST, Bordetella cgMLST v1. 0 (see above) and virulence genes schemes, the Pasteur database was designed for the sole initial purpose of Bordetella pertussis genotyping, with a Bp-specific cgMLST scheme and a Bp-virulence genes schemes  [29]. To merge the data available in the two databases, we proceeded as follows. As per BIGSdb dual design, isolates genomes and provenance data were imported into the "isolates" database, whereas allelic definitions of MLST, cgMLST and virulence genes were imported into the "seqdef" database. Regarding the isolates database, we first dumped the Oxford database and uploaded it on the Institut Pasteur server.
If two or more isolates were identified as the same strain, they were attributed the same duplicate number, consecutively. Duplicated data identification was based on a combined analysis of metadata and phylogeny tree reconstruction. At time of merging and closure, the Oxford database comprised 1,914 isolates entries, 57 of which were private, whereas the Pasteur database comprised 2,180 entries, 2,009 of which were private. As of January 7 th , 2022, the platform resulting from the merger comprises 2,581 public isolates entries, and 4,853 isolates in total when considering private entries.
cgMLST schemes Two core genome MLST schemes are available. The first scheme, Bordetella cgMLST v1. 0 (hereafter referred to as cgMLST_genus), was initially defined and hosted in the Oxford platform and was designed to be applicable for the entire Bordetella genus. The second scheme, called cgMLST_pertussis, was originally hosted in the Pasteur database and was built for B. pertussis isolates genotyping only  [29]. Note that only the latter scheme has attached cgST definitions, i. e. , unique cgST identifiers are attached to each distinct allelic profile. Both cgMLST schemes are available in the merged library.
Genotyping schemes for vaccine antigens and virulence-associated genes In both original databases, virulence-associated gene schemes had been defined separately. We choose to keep all loci from the virulence scheme designed in Oxford and to add some additional relevant loci. These loci were then grouped into different schemes comprising either Bp vaccine antigens (fim2, fim3, ptxP, ptxA, ptxB, ptxC, ptxD, ptxE, fhaB-2400_5550), T3SS genes (bopB, bopD, bopN, bsp22, bteA), autotransporters (bapC, brkA, tcfA, prn, vag8), other toxins (cyaA, dnt) or phase biology genes (bipA, bvgA, bvgS). We decided to include the prn locus in the autotransporter scheme rather than in the Bp vaccine antigens scheme, because prn-negative isolates would not allow the definition of sequence types (ST) for the vaccine antigens scheme.
To make analyses of virulence-associated and vaccine antigen genes more user-friendly, common gene names used in the literature were used as locus identifier, instead of the locus tags that were initially used in the Oxford database (e. g. , BORD005020 was replaced by fim2 and BORD005021 by fim3). In addition, for five loci common to the original Pasteur and Oxford databases (i. e. fim2, fim3, ptxA, ptxP and tcfA), the allele numbering was re-defined so that the alleles of each locus would match the nomenclature found in the literature for B. pertussis alleles; the correspondence between the original allele numbering system and the new one is defined in Table  S1. Subsequently, the numbering of alleles was simply incremented as new genomes scans led to novel allele definitions.
Criteria for loci associated with virulence were stricter: only new alleles sharing 90% identity, 90% alignment with a type allele and with a complete CDS were recorded (excluding the ptxP promoter locus and the fhaB fragment fhaB-2400_5500). These strict parameters were used to minimize the detection of paralogous sequences and to exclude decaying alleles. For each species, we defined one or two reference strains taken either from literature or from the NCBI RefSeq database (Table  S2 ). Type alleles were defined from each reference isolate in order to constrain the search space so as to ensure future consistency of allele definitions. The definition of new alleles was subject to constraining parameters. To detect alleles, BLASTN thresholds were set to 90% of identity, 90% of alignment length coverage, and considering only the complete coding sequences (except for the ptxP locus promoter and the 23S rRNA gene, which are not protein CDSs).
Phylogenetic analyses Phylogenetic analyses were performed based on concatenated alignments of individual gene loci defined in the database. We used an in-house script which combines IQtree (IQ-TREE 2. 0. 6, model substitution GTR+G+I) and Gubbins (2. 4. 1, default parameters)  [44, 45]. Phylogenetic trees were drawn and annotated using iTOL and FigTree  [46, 47]. To include the breadth of currently sampled Bordetella diversity, we first downloaded all genomic sequences from public databases and ran a rapid distance based phylogenetic analysis. From this, we retained all representative genomes of unique branches and downsampled shallow branches that were represented multiple times. The resulting dataset included the putative novel species initially described as genogroups by Spilker et al.
on the basis of nrdA gene sequences  [21]. The Bordetella diversity dataset is publicly available from the genomic library as project Bordetella genus phylogeny (https://bigsdb. pasteur. fr/cgibin/bigsdb/bigsdb. pl?db=pubmlst_bordetella_isolates&page=query&project_list=23&submit =1). To analyze the phylogenetic structure within the BbGS, we selected 204 isolates: 177 B. bronchiseptica representative of the clonal complexes I and IV  [1]  and 9 others that did not belong to these complexes. This dataset was completed with strains from B. pertussis (n=9) and B. parapertussis (n=9), selected to represent the known diversity within these two taxa: for Bp, lineage I (strains B0887 and 18323) and lineage II (which includes ptxP1 strains as including Tohama, and ptxP3 strains)  [23] ; and for B. parapertussis, the ovine lineage (strain Bpp5) and the human lineage reference strain 12822.
A public project encompassing all selected genomes is available in the BIGSdb genomic library platform (project name: B. bronchiseptica phylogeny; URL: https://bigsdb. pasteur. fr/cgibin/bigsdb/bigsdb. pl?db=pubmlst_bordetella_isolates&page=query&project_list=24&submit =1). In the same way, 124 Bp isolates selected to represent Bp genomic diversity were used to analyze the phylogenetic position of macrolide-resistant isolates. To this aim, we selected isolates representative of main ptxP branches (ptxP alleles 1, 2, 3, 19 and 21) and all genomes of isolates known to be resistant to erythromycin (n=51). The dataset is publicly available from the genomic library as project B. pertussis phylogeny (https://bigsdb. pasteur. fr/cgibin/bigsdb/bigsdb. pl?db=pubmlst_bordetella_isolates&page=query&project_list=25&submit =1).