dataesr/scientific-paragraphs-categorization huggingface dataset:
Interim results The interim analysis was performed, including all data up to November 23, 2016, with 105 PFS events confirmed by central review assessment, a higher number of events than initially planned for the interim analysis (N ¼ 93). At that time, 194 patients had been randomized (127 to niraparib, 67 to physician's choice). The primary endpoint was assessed in the 185 patients with a centrally confirmed germline BRCA mutation (121 in niraparib arm, 64 in physician's choice arm). The median duration of PFS by central review was 4. 0 months in niraparib arm and 4. 6 months in physician's choice arm, with an HR of 1. 15 (which was higher than the updated futility boundary of 0. 884; Fig. 2A ). Local assessment of PFS resulted in an HR of 0. 69 (95% CI, 0. 46-1. 02) favoring niraparib (Supplementary Fig.
Final results The final analysis was performed, including all data up to December 1, 2017. Among 206 patients in the centrally confirmed germline mutation carrier population (135 in niraparib arm, 71 in physician's choice arm), 135 PFS events were observed per the independent central review. The median duration of PFS by central review was 4. 1 months in niraparib arm and 3. 1 months in physician's choice arm (HR, 0. 96; 95% CI, 0. 65-1. 44; stratified log-rank P value: 0. 86; Fig. 2B ). PFS as assessed by the investigator resulted in a median local-PFS of 5. 0 months in the niraparib arm and 3. 1 months in the physician's choice arm (HR, 0. 65; 95% CI, 0. 46-0. 93; Supplementary Fig. S1 ). No differential benefit was detected in any of the pre-planned subgroup analyses (Fig. 2C ). Results from sensitivity analyses were all consistent with the primary analysis (Supplementary Table  S6 ).
Acknowledgments The BRAVO trial was funded by  TESARO , the trial sponsor. We would like to thank the patients, physicians, nurses, and trial coordinators who participated in the BRAVO trial. The BIG member groups that participated in the BRAVO trial:  Borstkanker Onderzoek Groep (BOOG) ,  European Organisation for Research and Treatment of Cancer-Breast Cancer Group (EORTC/BCG) ,  Spanish Breast Cancer Group (GEICAM) ,  Italian Oncology Group for Clinical Research (GOIRC) , Hellenic.
Clinical strain sequencing Each clinical strain was identified by microscopy for its genus and by sequencing for its species complex. The β-tubulin (Btub1F/Btub2R) and calmodulin (CMD5/CMD6) genes were sequenced for Aspergillus strains  [10]  , β-tubulin (Bt2a/Bt2b) and D1/D2 (NL1/V3-12) for Scedosporium strains  [11]  , and elongation factor (EF1/EF2) for Fusarium strains  [12]  ( Table  2  ). Following DNA extraction, PCR was performed in an iCycler iQ5 TM (Bio-Rad) using a TaqPurple Kit (Ozyme) with primers specific for each genus. Sequencing according to the Sanger method was carried out by GenoScreen (France) using primers used to perform PCR. Sequence analyses were interpreted using BioEdit software  [13]  and were compared with the Mycocosm. jgi. doe. gov and Aspergillusgenome. org databases for species complex identification.
Acknowledgments The authors would like to thank  Septeos Company  for funding this study as well as the  French Ministry of Higher Education and Research , the  Université de Lorraine , and the  CPER IT2MP (Contrat Plan État Région, Innovations Technologiques, Modélisation & Médecine Personnalisée)  and  FEDER (Fonds européen de développement régional). The authors acknowledge the support of the Stress, Immunity, Pathogens unit by the ' Impact Biomolecules' project of the 'Lorraine Université d'Excellence'(Investissements d'avenir -ANR ).
Samples were eluted isocratically with 95% (v/v) of CH3CN in water which contain 0. 5 mM of citric acid with a flow rate of 0. 1 mL/min. The instrument was operated in positive electrospray ionization mode and all aspects of analysis were controlled using LabSolutions software (version 5. 54, Shimadzu). Ionization was performed with the following settings: capillary voltage 4 kV; cone voltage 10-20 V; source block temperature 200 °C; desolvatation line (DL) temperature 150°C with a nitrogen flow of 3L/min. Nitrogen was used as desolvatation gas and argon as collision gas. Optimization of MS/MS transitions. Samples were first analyzed by scan mode. Ions of interest were then fragmented to obtain daughter scans. Based on different fragmentations, specific multiple reaction monitoring (MRM) transitions were optimized.
One transition was monitored for each analyte. The adducts formed by 1,2-NphQ gave transitions corresponding to 425. 2>224. 1, 424. 1>307. 8 and 308. 1>266. 9. The collision energy in V for each adduct was -10, -19, -14 and -5, respectively. For data acquisition, a time segment approach was used to arrange the transitions based on retention time, enhancing method sensitivity for detection. HRMS experiments. Structure confirmation was realized with a Waters Acquity UPLC I-Class system coupled with a Vion IMS QTof mass spectrometer (Waters). The 2 µL injection were performed on a Waters UPLC HSS C18 SB column (1. 8 µm, 1 mm x 150 mm) with a flow rate of 0. 2 mL/min. The column was thermostated at 30°C during analysis. Samples were eluted in isocratic elution mode with water containing 0. 1 % formic acid and acetonitrile with 0.
1 % formic acid (20:80; v/v). The instrument was operated in positive electrospray ionization mode and UNIFI Scientific Information system was used for data acquisition and processing. Mass spectrometry conditions were: capillary voltage 1. 5 kV, cone voltage 40 V, cone gas flow 50 L/h, source temperature 90°C, source offset 80 V, desolvation gas temperature 350°C and desolvatation gas flow 800 L/h. Kinetics of adduct formation. 1,2-NphQ (24 mg, 0. 15 mmol) in 2,5 mL of DMF was mixed with 2'-dG (27 mg, 1 mmol) in 5 mL of total reaction mixture. This reaction was realized in the dark at 4 °C, 25 °C, 37 °C, 43 °C and 50 °C for 0. 25, 0. 5, 1, 2, 4, 6, 24, 27, 31, 48, 52, 55, 72, 76, and 80 h. At each point, the levels of DNA adducts were measured by UHPLC-MS/MS.
EmrE Protein Databank (PDB) entry: 3B5D; DinF-BH PDB: 4LZ9; MdfA PDB: 4ZOW; MexAB-OprM EM Data Bank (EMDB) entry: EMD-10395, PDB: 6TA6; EmrAB-TolC adapted from Yousefian et al. ;  9  MacAB-TolC EMDB: EMD-3652, PDB: 5NIK; MacB EMDB: EMD-3653, PDB: 5NIL. The HlyB model (based on PCAT1 (PDB: 4RY2)) and the full assembly of the HlyD-docked homology model are provided by V. Bavro. LPS, lipopolysaccharide. we would like to highlight the structure of this manuscript. It is organized into four major divisions, which cover first the biological roles of the tripartite pumps including their contribution to antimicrobial resistance, as well as their genetic organization and regulation (sections 2-4). The second group of sections (5-7) deals with the molecular organization of the individual components of the tripartite complexes, with particular effort being put into highlighting the modularity and similarities in the structural organization of the different transporter groups, notably the ABC and RND families (sections 5.
ABC Transporter Family The ATP-binding cassette (ABC) transporters are an extremely diverse superfamily of transporters with equally diverse functions within the cell that are widespread across both pro-and eukaryotic organisms. Classified as the TC# 3. A. 1 by the transporter classification database, TCDB (http:// www. tcdb. org),  418 the ABC superfamily forms the largest functional superfamily of primary active transporters known, and in Escherichia coli alone 79 ABC proteins have been identified, making the ABC transporters the largest paralogous family of proteins in its genome comprising 5% of its total,  419  forming 69 independent functional systems, with some 57 being ABC transporters. 129, 420 Several different classification systems have been proposed over the years to address this diversity within the family, see refs 421-423, taking into account both functional and topological data.
423 The known structures of the latter group include MacB itself,  24, 272, 431  as well as the heterodimeric LolCDE lipoprotein sorting system (LolC, PDB ID 5NAA;  432  LolE, PDB ID 5UDF  432  ) and the FtsX family members (PDB ID 4N8N; 6HEE, 6HFX). 433, 434 n addition, the maintenance of phospholipid asymmetry (Mla) MlaFEDB complex,  435, 436  the structure of which has recently become available (PDB ID 7CGN; 7CH0; 7CGE; 6XBD),  [437] [438] [439]  revealed unexpected structural organization of the MlaE transmembrane domain, which might merit its isolation into a new, separate topological group. As the ABC transporters are subject to a number of reviews (see refs 423 and 440), including in the current special issue of Chemical Reviews itself,  441  to avoid redundancy, below we will focus on aspects of the organization of the ABC transporters that are specific to their function within the context of the tripartite assemblies.
63, 462 Both McjD and YojI require the action of the OMF TolC for the export of MccJ25, although it is not clear whether any of them participate in bona f ide tripartite systems or there is a soluble intermediate of transport. 63, 462 he structure of the McjD (PDB ID 4PL0)  459  is representative of the type IV family of ABC transporters, sharing close topological and structural similarity to other canonical type IV transporters, such as Sav1866,  463  MsbA,  464  and Pgp/ABCB1 465 (Figure  12 ). The structure of the biological unit is homodimeric (overall dimension of ∼125 × 55 × 50 Å), with each protomer composed of an N-terminal TMD composed of 6 TM-helices and a C-terminal NBD. The TM-helices are connected by extracellular and intracellular loops, with the intracellular loops between TM2 and TM3 and between TM4 and TM forming the "coupling helices" CH1 and CH2, respectively.
The binding of the ATP to the NBDs at this point was proposed to bring the transporter into a hypothetical substrate-engaged occluded conformation (Occ), and it is supposed to transit into a nucleotide bound outward-facing open (OF) conformation. Upon release of the substrate, the transporter was suggested to adopt an the outward occluded (Occ) conformation yet again, however this time in a substrate free state. The structure solved (PDB ID 4PL0)  459  was associated with this post-transport occluded stated, and subsequent ATP-hydrolysis and release of the bound ADP and Pi eventually resets the transporter to the initial (IF o ) configuration completing the cycle. Later the structure of the eukaryotic P-gp (ABCB1)  465  has been used to further refine this cycle. Further research, adding pulsed electron-electron double resonance (PELDOR) and single molecule Forster-resonance energy transfer (sm-FRET) measurements to probe the conformational changes and the dynamics of McjD along its transport cycle,  461, 482  has led to the suggestion that irrespective of the presence or absence of nucleotides, in the absence of MccJ25, McjD remains in an occluded conformation and that it requires both MccJ25 and ATP to open, presenting a mechanism for the substrate transport and selectivity that was dubbed the "occluded-mechanism with transient opening".
449 Concomitant with the secretion of the T1SS substrate into the extracellular medium, the GG-repeats bind Ca 2+ ions with high affinity, triggering cargo-domain folding. 500, 501 he C39-domain (Interprot ID IPR005074) belongs to the MEROPS 502 peptidase cysteine-proteinase family CA,  483, 503  which includes proteins with a papain-like fold. This homology-based prediction was confirmed, when the C32 and H105-residues of the N-terminal C39-domain of CvaB transporter were shown to be critical for the calciumdependent cysteine protease activity and the secretion of its native cargo colicin V. 504  The crystal structure of the C39 domain belonging to the bacteriocin-associated ATPase ComA from Streptococcus provided a structural template to the family (PDB ID 3K8U). 484 The structure revealed a domain consisting of two subdomains with the active site sandwiched between them.
The smaller subdomain consists of a bundle of three consecutive N-terminal α-helices, with the catalytic C17 located at the end of the first of them, and is positioned on top of a larger subdomain, that presents a twisted antiparallel βsheet core (β1-β6) supplemented by two small α-helices (α4 and α5), and is contributing the active site residues H96 and D112, consistent with a classical catalytic triad for CA cysteine proteinases. 484, 503 A fourth residue preceding the catalytic cysteine, in this case Q11, forms a part of an oxyanion hole that stabilizes the acyl-intermediate formed during catalysis (see Figure  13 ). 484 he recent structure of the protease domain of the PCAT transporter LahT from a lanthipeptide biosynthetic operon in the Gram-positive Lachnospiraceae bacterium C6A11 in complex with a leader peptide (PDB ID 6MPZ)  507  provides a model for the substrate recognition, where the helical region of the substrate peptide is oriented in a small groove located between the C39 domain and the NBD of the transporter, providing an effective means to lock these domains together.
In addition, the leader peptide may serve as a backstop that prevents the cleaved cargo from sliding back into the cytoplasm and thus provides the directionality of transport upon binding of ATP to the NBDs. C39-domains have also been revealed in the structures of the PCAT1 transporter both in the nucleotide free apo-state (PDB ID 4RY2), in the ATP-analogue occluded state (PDB ID 4S0F),  273  and in complex with the cognate substrate CtA peptide (PDB ID 6 V9Z),  505  all showing close correlation with the one seen in CvaB and confirming the earlier cargo-binding model derived from the isolated C39-domain  507  (Figure  14 ). As predicted, the peptide signature sequence (Leu(-12)-(X) 3 -Glu(-8)-Leu(-7))  484  makes a number of specific interactions based on the conserved residues in the C39-domain which facilitates its orientation for processing (Figure  14 , panel E).
508 The N-terminal domain of HlyB shares ∼40% homology to C39 peptidases, but critically, this "C39-like domain" or CLD displays a degenerated proteolytic site, with a catalytically essential cysteine  504  being replaced by a tyrosine (Y9). 509 onsistent with this, HlyA does not contain an N-terminal leader peptide or a GG motif and is not cleaved during or after the transport, suggesting an alternative mechanism is in action for its secretion. Compared to the catalytical histidine of ComA-PEP (H96), the equivalent histidine of the HlyB-CLD (H83) is flipped by 180°and the solution NMR structure of the HlyB-CLD (PDB ID 3ZUA)  506  revealed a π-π stacking between the H83 and W77 residues, which might be a characteristic feature of CLDs, as the tryptophan residue in the equivalent position is conserved across the family.
,  506  HasD does not possess an N-terminal domain. Furthermore, the cellular chaperone SecB is required for the productive HasA secretion by the T1SS by inhibiting its folding and maintaining the unfolded, secretion-competent state of HasA. 513 Nevertheless, HasA contains primary recognition sites that interact with HasD prior to the secretion, likely within the substrate binding cavity of the transporter, although their exact identity remains obscure. 512 Other notable members include LipB from the S. marcescens lipase T1SS (UniProtKB Q54456)  514  and PrtD from the protease secretion system PrtDEF from Aquifex aeolicus VF5 (UniProtKB O67184),  515  both of which are discussed below. 5. 6. 6. NBDs of PCAT Transporters. The NBDs of HlyB (PDB ID 1XEF,  509  PDB ID 2FF7  516  ), LipB (the ABC transporter involved in the T1SS that secretes the lipase LipA in S.
marcescens) (PDB ID 5X7K),  514  and PrtD (PDB ID 5L22)  515  have been solved and present a structure that is generally identical to that of the canonical type IV ABC transporters. ATP-binding promotes dimerization of the HlyB-NBD. 517 Indeed, the HlyB NBDs has been solved in an ATPbound state (PDB ID 1XEF),  509  presenting a dimer in which two intact ATP molecules are bound at the interface of the Walker A motif and the C-loop provided by the opposite protomers (Figure  15 ). Biochemical data suggests a mechanism of substrate-assisted catalysis, rather than that general base catalysis might operate in the HlyB-type ABC-ATPases. Two highly conserved residues, namely E631 and H662, form a catalytic dyad, with H662 playing the role of a "linchpin", that coordinates a complex network of intermolecular interactions, and were found to be required for interprotomer communication, that covers ATP, water molecules, as well as Mg 2+ ions and amino-acids both in cis and trans orientation (Figure  15 ).
509  couple of follow-up studies  516, 518  revealed the kinetics of ATP-driven NBD association alongside the structures of the ADP-bound form of HlyB NBD, in wild-type (PDB ID 2FF7), as well as in mutant forms of the transporter (PDB ID 2FFA; 2FFB) allowing us to complete the functional cycle of the transporter. Cavity analysis of dimeric ATP-bound NBDs indicates that inorganic phosphate should not be able to diffuse freely out of the binding site, and its exit requires an additional conformational change in the domain. 516  Intriguingly, these structures also revealed a structural asymmetry within the ATP-bound NBD dimer in the form of one open and one closed phosphate exit tunnel. Thi  tunnel gate is controlled by a salt bridge between D551 and a R611-residue, the side chain of which flips open to allow diffusion of the inorganic phosphate.
coli HlyA, Ca 2+ ions bound by conserved D residues within the BIg domains stabilize the protein and facilitate secretion. 527, 528 Exporting such cargoes would require a departure from the classical "alternate access" mechanism discussed above in favor of some form of continuous threading. Furthermore, several lines of experimental evidence suggest that T1SS substrates must be unfolded in order to be translocation competent,  529, 530  resulting in the length of an unfolded T1SS substrate that would far exceed the length of the transporter TMD cavity itself. These observations imply that T1SS ABC transporters must operate by a distinct mechanism, where the unfolded polypeptide is likely progressively threaded through the TMD of the transporter over multiple ATP-hydrolysis cycles. 3, 449, 512 hese hypotheses were confirmed by the structure of the first ABC transporter associated with T1SSnamely the Aquifex aeolicus PrtD (AaPrtD) coded by the abcT5 gene (PDB ID: 5L22; UniProtKB: O67184).
432 All of the permease domains of the proteins described above contain the 4 TM-helix architecture of the MacB. However, more exotic architectures have also been described, e. g. , the bacitracin-sensing and resistance-associated BceAB-type transporters  577  that appear to have 10 TM helices arising from a duplication of the 4-TM FtsX fold over TM2-4 and 7-10 and featuring a central helical insertion over TM5-6. These transporters presumably function as monomeric units. Some other members of the family feature this arrangement, e. g. YbbP-YbbA 2 complex; 442 however, these have been poorly characterized. The first glimpse of the 3D structural organization came from the periplasmic domain of the Aggregatibacter (previously Actinobacillus) actinomycetemcomitans (PDB ID 3FTJ),  578  which revealed a structural organization distinct from the then available ABC transporter structures.
In the past decade, the structural and conformational space for type VII transporters has expanded dramatically to include the complete MacB from several different species of Gram-negative bacteria,  24, 272, 431  as well as the Gram-positive homologues Spr0694-0695 from Streptococcus pneumoniae (PDB ID 5XU1)  571  and YknWXYZ from Bacillus amyloliquefaciens (PDB ID 5F9Q). 579 In addition, the related heterodimeric LolCDE lipoprotein sorting system (LolC, PDB ID 5NAA, 6F49;  432  LolE, PDB ID 5UDF (Abendroth et al. , to be published)) and the FtsX family members (PFAM family FtsX (PDB ID 4N8N, 6HEE, 6HFX)  433, 434  have also been determined. Importantly, the complete assembled structure of the tripartite MacAB-TolC from E. coli has also become available (PDB ID 5NIL, 5NIK),  272  allowing a direct comparison with the RND-based assemblies.
5. 7. 5. Periplasmic Core Domains (PCDs). As mentioned above, the bulk of the periplasmic portion of the type VII ABC transporters is contributed by a globular "periplasmic core domain" or PCD. 578 It forms a conserved module, which is presented across the MacB and also FtsX-type transporters  574, 575  allowing to unite them into a separate PFAM group (PF02687) and giving the name to the whole family, so it can often be referred to as MacB/FtsX. The PCD domain could be split into an "upper" and "lower" subdomain,  578  which have also been named periplasmic subdomain C (PSC), and periplasmic subdomain N (PSN), respectively  272  (Figure  20 ), with the lower portion presenting a mixed α-β sandwich of a general (β-α-β-β-α-β) configuration, sharing high structural homology to the porter (PD) domains of the RND transporters,  578  while the "upper subdomain", which has become known as the "SABRE" (an acronym for small, alpha/beta rich, extracytoplasmic), is unique to the wider FtsX family and can vary significantly in structure.
In some of the recent literature, the PD and SABRE subdomains have also been referred to as periplasmic subdomain N (PSN) and periplasmic subdomain C (PSC), respectively,  272  but to avoid confusion, we will stick to the PD and SABRE nomenclature (Figure  20 ). Due to its variability, the SABRE subdomain can be used as a differentiator within the wider MacB/FtsX family, and based on this it is possible to subdivide the group into several cohorts. It is notable that in the prototypical members of the MacB family, including the Aggregatibacter actinomycetemcomitans AaMacB,  431, 578  Acinetobacter baumannii AbMacB, 24 E. coli EcMacB,  272  and the Gram-positive transporters belonging to the family, such as the Streptococcal permease Spr0695 (PDB ID 5XU1),  571  the SABRE domain presents a continuous entity, which is spliced into the middle of the "lower subdomain" (PD), splitting it evenly into two β-α-β motifs.
434 The PCD of FtsX reveals an upper extended βhairpin and a lower α-helical lobe, with each extending from a mixed α-β core. The helical lobe mediates a physical interaction with the peptidoglycan hydrolase PcsB via the coiled-coil domain of PcsB. Within the classical FtsX family transporters the mycobacterial homologues (e. g. , PDB ID 4N8N)  433  could be considered a basal group, and there the SABRE domain is presented by a simple helical extension, while the FtsX from Streptococcus pneumoniae (PDB ID 6HFX; 6HEE; 6HE6)  434  presents an additional β-hairpin insertion between β1 and α1 (see Figure  21  for a comparison of SABRE domains). Intriguingly, exactly the same expansion of the basic PD-module can be found in the C-terminal domain (CTD), the PD1-domains of the eukaryotic RND-related cholesterol transporter NPC1 (e.
g. , PDB ID 5U74,  585, 586  6W5R,  587  and 6UOX  588  ), as well as the second extracellular domain (ECD-II) of the Hedgehogsignaling associated Patched1 (PDB ID 6OEU)  589  and the recently resolved Dispatched (DISP1) (PBD ID 6XE6)  590  showing the topological versatility of the basic PD-fold. The recent structure of the EnvC bound to the periplasmic domain of FtsX (PDB ID 6TPI)  591  reveals an EnvC-FtsX complex with 1-to-2 stoichiometry with two distinct FtsXbinding sites located within an antiparallel coiled-coil domain of EnvC, showing that the FtsX-PD modules could be used not just to provide lipid-and PG-binding but can mediate protein-protein interactions. In Gram-negative bacteria the inner-membrane-associated LolCDE ABC transporter, the LolA chaperone, and the LolB outer-membrane receptor form an essential system for membrane extraction and transportation of the newly produced lipoproteins from the outer leaflet of the plasma membrane to the inner leaflet of the outer membrane.