dataesr/scientific-paragraphs-categorization huggingface dataset:
Key elements of comparison with other distributed products In this study, we highlight key features that make our approach to denoising SLA data different and more attractive than the approaches currently used in other distributed prod-ucts. It relies on (1) the EMD algorithm that adaptively splits the SLA signal into a set of empirical functions that share the same basic properties such as wavelets, but without having to conform to a particular mathematical framework; (2) a denoising algorithm that relies on a thorough and robust analysis of the local Gaussian noise affecting the SLA data over the entire wavenumber range; (3) an ensemble-average approach to estimate a robust denoised SLA signal and its associated uncertainty; (4) a calibration of the method to provide a realistic distribution of SLA variability by adjusting the mean level of the PSD function.
Data availability The SASSA data set https://doi. org/10. 12770/1126742b-a5da-4fe2-b687-e64d585e138c (Quilfen and Piolle, 2021)  is freely available on the CERSAT website at ftp: //ftp. ifremer. fr/ifremer/cersat/data/ocean-topography/sassa (last access: 28 March 2022). The altimetry observations used are obtained from the Copernicus Marine Environment Service and are available at https://resources. marine. copernicus. eu/product-detail/SEALEVEL_GLO_ PHY_L3_MY_008_062/INFORMATION  (Taburet et al. , 2021). Ancillary data are provided by the Sea State Cli-mate Change Initiative products processed at the Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER) and are available on the ESA CCI website at ftp://anon-ftp. ceda. ac. uk/neodc/esacci/sea_state/data/ (last access: 28 March 2022,  Dodet et al.
(A1) and then E n verifying Eq. (2) in order to compute the thresholds with Eq. (3) for denoising each IMF; (2) to obtain the high-frequency noise series similar to that of the IMF1 of a WGN, which will be used to generate a set of noisy signals and associated denoised signals whose average and standard deviation finally provides the denoised SLA signal and its associated uncertainty, respectively. Figure  2  show the PSDs of the high-frequency noise estimated from the SLA IMF1 (green curves), which show very good agreement with the PSDs of the white noise IMF1s. The IMF1 processing has been tested using different wavelet denoising algorithms available in the MATLAB package, but the best result was obtained using the wavelet shrinkage method of  Huang and Cressie (2000). These authors developed a Bayesian approach to denoising various signals, assuming that it can be the sum of the underlying targeted signal composed of a piecewise-smooth deterministic part and a stochastic part, plus a noise as a zero-mean stochastic part.
Genotype data All cohorts performed genotyping on Illumina or Affymetrix arrays and imputed to the 1000 Genomes Project reference haplotypes. 15 Most studies used the Phase I Integrated Release Version 3 reference panel (2010-11 data freeze, 2012-03-14 haplotypes), which contains haplotypes for 1,092 individuals of all ethnic backgrounds. 15 Information on genotype and imputation for each study is presented in Table  S3. Although we refer to the analyzed variants as SNPs, the imputed data also include indels (insertions and deletions).
Study-specific statistical analysis We considered three statistical models to satisfy slightly different purposes:  12  Model 1 is a joint effect model and is our primary model. It represents the joint analysis of the effects of the SNP, psychosocial exposure, and their interaction: E½BP ¼b 0 þ b SNP SNP þ b E E þ b SNPÃE SNP Ã E þ b C C where E is the psychosocial variable and C represents all covariates (including age, sex, cohort-specific variables, and principal components [PCs]). PCs were derived from the directly measured genotype data and adjusted as appropriate for each study population. Information on PCs and additional study-specific covariates included in each analysis is provided in Table  S3. Each SNP was coded under the assumption of an additive model. The model incorporated a SNP 3 Psy interaction effect.
1). Variants with p < 1eÀ5 in 1-df or 2-df tests in any meta-analysis and any of the three models were selected for stage 2 analyses. In the focused discovery stage 2, only $20,000 variants were investigated, and we used the same approaches as in stage 1 to perform ancestry-specific and trans-ancestry meta-analyses but without genomic control correction or variant filtering. The $20,000 variants were examined for association with the 4 BP traits, in the context of the 3 psychosocial factors and in each of the 5 ancestry groups using the joint effect model (model 1). Finally, we performed ancestry-specific and trans-ancestry metaanalyses of all the cohort-level data from stage 1 and stage 2 together (model 1 only). There was no variant filtering at that stage, and all available data from stage 1 and stage 2 were used.
We computed false discovery rate (FDR) adjusted p values (qvalues) for the 2-df test using the p. adjust function in R, correcting for the number of analyses performed in stage 1 (4 BP traits, 3 psychosocial factors, and 5 þ 1 ancestry/trans-ancestry groups). SNPs with p < 5eÀ8 and q < 0. 05 and without any evidence of heterogeneity (p Het > 0. 05) in ancestry-specific meta-analyses for either the 1-df or 2-df test were considered statistically significant. We defined a locus as the 51 Mbp region surrounding an index SNP and a novel locus as 51 Mbp away from an index SNP previously reported in the GWAS catalog and in Evangelou et al. 3  Proportion of variance explained We used the VarExp R package  20  to estimate the proportion of variance in each BP trait explained by previously reported BP variants and newly identified SNPs.
23 We also used the Pheno-Scanner v2  24  database to evaluate our novel BP-associated SNPs for association with diseases and traits, metabolites (metabolite quantitative trait loci, mQTL), gene expression (eQTL), proteins (protein quantitative trait loci, pQTL), and DNA methylation (methylation quantitative trait loci, methQTL). Finally, we carried out protein-protein interaction networks and pathways enrichment analyses using STRING v. 11. 25.
Known BP loci The remaining 1,609 SNPs reaching genome-wide significance mapped within 1 Mbp of 50 previously reported BP SNPs. These were mostly identified in European ancestry samples. Of the 1,609 SNPs, 117 showed nominally significant interaction effects (1-df p < 0. 05), and these were mostly observed in African ancestry samples or trans-ancestry meta-analyses (Table  S5 ). We further assessed gene-psychosocial factor interactions on BP at previously known loci 3 in our dataset. Of 983 previously reported BP loci, 976 were present in our meta-analyses of stages 1 and 2. After harmonization of risk alleles against the previously published results, we tested for interaction in the 976 index SNPs. A Bonferroni-corrected p value threshold controlling for the number of SNPs tested (976), the number of BP traits (4), the number of Psy traits (3), and the number of ancestry groups (5) was used.
] [64]  Currently ve classes of lanthipeptides have been reported that differ in the biosynthetic enzymes that carry out (Me)Lan formation. New knowledge reported on these enzymes is briey discussed in the following sections for class I-IV. The recent discovery of the lanthidins (Section 2. 17) revealed the latest independent pathway to lanthionines (class V),  54, 56, 57  which at present is not yet well understood. 3. 1. 1 Class I lanthipeptide biosynthesis 3. 1. 1. 1 Class-dening enzyme: aminoacyl-tRNA dependent dehydratase. In vitro reconstitution of the biosynthesis of class II-IV lanthipeptides had been reported prior to 2013, 1 but reconstitution of class I biosynthesis had proven recalcitrant. The explanation for this difficulty came when it was revealed that dehydration by the LanB dehydratases (InterPro families IPR006827 and IPR023809) during class I lanthipeptide biosynthesis requires glutamyl-tRNA, a co-substrate that was not anticipated (Fig.
19B ). 49 The discovery of the requirement of glutamyl-tRNA had been foreshadowed by targeted mutagenesis of the NisB enzyme, the LanB involved in nisin biosynthesis, which resulted in glutamylation of Ser and Thr residues in the precursor peptide, NisA, during heterologous expression in Escherichia coli. 65 Reconstitution of the dehydration activity in vitro required the macromolecular fraction of E. coli cell extract, A crystal structure of the dehydratase NisB bound to the LP of its substrate NisA (Protein Databank, PDB: 4WD9) demonstrated the enzyme contained three domains (Fig. 20A ). 49 One domain (InterPro family IPR006827) catalyzes the transfer of glutamate from the tRNA to the peptide substrate. Then, the glutamylated peptide is translocated to another domain (InterPro family IPR023809) in which the glutamate is eliminated to form Dha/Dhb.
A ping-pong type mechanism in which the glutamyl group is rst transferred from the glutamyl-tRNA to the enzyme prior to transfer of the glutamyl moiety to the Ser/Thr in NisA was ruled out by mutagenesis. The LPbinding domain in NisB 49 (termed the RiPP precursor Recognition Element, 66 RRE) will be discussed further in Section 4. 1. 1. Structure elucidation with a non-reactive analog of glutamylated NisA (PDB: 6M7Y) identied the elimination active site of NisB (Fig. 20B ), while the glutamyl transfer active site is inferred based on a structure of a biosynthetic enzyme that carries out Glu-tRNA dependent glutamylation of Ser residues during thiopeptide biosynthesis (see Section 3. 2). 67 Covalent attachment of the LP to the RRE demonstrated that catalysis can take place with the LP occupying only a single binding site  ruling out models in which the LP needs to move during catalysis.
68 tudies with LanB enzymes from different bacterial phyla have shown that the nucleotide sequence in the acceptor stem of the tRNA Glu is critical for the enzyme to accept the cognate glutamyl-tRNA as substrate,  69, 70  an observation that explains difficulties in heterologous expression of many class I lanthipeptides. Some RiPP BGCs, such as those of the antifungal pinensins  63  or the thiopeptides, 71 contain split LanB dehydratases (see Section 3. 2) in which glutamylation and elimination are carried out by separate polypeptides. Compared to advances in understanding the mechanism of dehydration and LP recognition, the mechanism of cyclization in class I lanthipeptides by LanC enzymes (InterPro family: IPR033889) remains to be investigated in detail. Cyclization has been shown to be reversible for both class I and class II systems,  72  but the mechanism of catalysis is not well understood.
Several studies reported prior to 2013 suggested that complex formation involving the dehydratase LanB, the standalone cyclase LanC, the LanA substrate and the LanT transporter is important for the overall PTM process. 1  Both LanB (Section 4. 1. 1)  49 and LanC 73 are believed to engage the same region of the NisA LP. The stoichiometry in these solution complexes has been suggested to involve one substrate per NisB dimer,  74  unlike the co-crystal structure of NisB with NisA where the stoichiometry is 1 NisB dimer: 2 NisA peptides. Thus, complex formation appears to result in a rearrangement that is currently not yet understood at the molecular level. 3. 1. 2 Class II lanthipeptide biosynthesis 3. 1. 2. 1 Class-dening enzyme: ATP dependent LanM synthetase. Class II lanthipeptides are biosynthesized by a bifunctional lanthipeptide synthetase (LanM, InterPro family: IPR017146).
22B ). 84 At present the stereochemistry at the additional chiral center of MeLab is unknown. The BGC of NAI-112 was identied and contains a gene for a glycosyltransferase. An interesting variant of class III lanthipeptides was discovered in which the N-terminus of a Lab-containing peptide was adorned with a fatty acid (see Section 3. 1. 5). 34 This class of compounds has been termed lipolanthines. lanthipeptides are generated by trifunctional enzymes called LanL that contain lyase, kinase, and cyclase domains (same InterPro families as LanKC: IPR000719 + IPR007822). At present only venezuelin and its congeners have been characterized, although genome sequences and synthetic biology studies suggest that other ring topologies can also be made by LanLcontaining gene clusters. 62, 85 Recent biochemical experiments showed that the LP of the precursor peptide binds to the kinase domain and that the dehydration process for venezuelin-like compounds occurs in an ordered and directional manner, from N-to-C terminus.
Thus, the RiPP segment of the lipolanthines are formed by previously reported features of lanthipeptide machinery: C-terminal decarboxylation by a LanD enzyme previously found in class I and II lanthipeptides (InterPro family: IPR003382; Section 5. 9), and dehydration and cyclization by a class III lanthipeptide synthetase to arrive at the novel avionin structure (Fig. 23B ). A follow-up study revealed 80 additional BGCs that were divided into four subtypes depending on the type of PKS or NRPS and on the presence or absence of a LanD. 88 LanKC enzymes encoded in BGCs that also encode a LanD were shown to be dependent on the LanD for labionin synthesis suggesting enzyme complex formation and/or allosteric regulation. 88 Biochemical insights into how the linkage of the FAS/PKS/NRPS product to the RiPP segment is formed have not yet been reported.
Thiopeptides: introduction and biosynthetic pathway Although thiopeptide biosynthesis had been studied at the genetic level, 1 in 2013 none of the core biosynthetic steps had been reconstituted in vitro. At a minimum, thiopeptide biosynthesis requires installation of thiazoles, dehydroamino acids, and cycloaddition of two dehydroamino acids. Biochemical studies on the biosynthesis of thiomuracin demonstrated a strict order of events in which the combined action of a cyclodehydratase (TbtG, YcaO InterPro family: IPR003776) and dehydrogenase (TbtE; InterPro family: IPR020051) (see Section 3. 4) with a designated LP-binding protein (TbtF) (see Section 4. 1. 1) results in the introduction of six thiazoles in an ordered, but non-directional process (Fig. 24 ). 71, 89 Only aer installation of these thiazoles does the dehydratase act on the peptide.
For micrococcin P1 biosynthesis, genetic studies suggest that prior to dehydratase activity, one additional PTM has to take place, the oxidative decarboxylation of a C-terminal Thr (Section 5. 9). 90 hiopeptide BGCs were known to contain a split dehydratase reminiscent of LanB lanthipeptide dehydratases. When the structure of the latter was reported (see Section 3. 1. 1), it became clear that the split genes in thiopeptide BGCs encode separate enzymes for Ser glutamylation and elimination to form Dha. The glutamylation enzyme TbtB from thiomuracin biosynthesis (InterPro family: IPR006827) required the use of tRNA Glu from the producing organism Thermobispora bispora, as Glu-tRNA from E. coli was not accepted. 71 TbtC (InterPro family: IPR023809) was then demonstrated to eliminate the glutamate to introduce four Dha residues in an ordered and directional process.
4). 92 Subsequently, SulD in close cooperation with SulEFG converts Thr5, Cys7, and Ser12 to the corresponding azoles. The authors show that a complex is formed by SulDEFG,  92  something that is likely a staple of many RiPP biosynthetic pathways. 93 The study of the sulfomycin biosynthetic enzymes illustrates that many different protein combinations may have evolved in thiopeptide biosynthetic pathways to achieve the same overall transformation as the more simple BGCs. 3. 2. 1 Class-dening enzyme catalyzes a [4 + 2] aza-cycloaddition. In 2015, the rst experimental conrmation was reported of the proposed [4 + 2] cycloaddition of two Dha residues to form the 6-membered nitrogenous heterocycle that is ubiquitous in thiopeptides. Exposure of a synthetic substrate that contained all anticipated thiazole and Dha residues to the enzyme TclM (InterPro family: IPR023809), resulted in cycloaddition to form the core scaffold of the thiopeptide thiocillin.
94 he same observations were made for the enzyme TbtD (an ortholog of TclM) with an enzymatically generated substrate. Analysis of the TbtD products demonstrated that the LP was eliminated as a C-terminal carboxamide. 71 Subsequent studies have demonstrated that only the last ten residues of the LP are required for efficient cycloaddition catalyzed by TclM and TbtD,  95  and that the latter enzyme can also catalyze the intermolecular [4 + 2] cycloaddition of Dha-containing peptides. 96 nterestingly, TclM and TbtD are homologous to TclC and TbtC, which, as discussed above, eliminate glutamate from glutamylated Ser to yield Dha. 97  A crystal structure of PbtD (an ortholog of TbtD involved in GE2270A biosynthesis) with a product analog bound (PDB: 5W99) provides some insight into the overall cyclization process,  97  but individual amino acids that catalyze the various steps involved in the [4 + 2] cycloaddition reaction and subsequent water and LP elimination have not yet been identied.
106 In the rst step, a member of the YcaO superfamily (InterPro families IPR003776 and IPR019938) associates with a partner protein belonging to the E1-ubiquitin activating (E1-like) superfamily and installs azolines in an ATPdependent manner. In roughly half of all known LAP BGCs, the E1-like and YcaO proteins are fused as a single protein, highlighting the importance of their collective effort in azoline installation. 107 Select azolines are subsequently oxidized to azoles by a avin mononucleotide (FMN)-dependent dehydrogenase, when encoded in the BGC. The LP is typically removed by a protease and the mature LAP is exported from the producing cell. Other ancillary modications such as methylation (Section 5. 3. 5), acetylation (Section 5. 9. 1), and dehydration (e. g. goadsporin,  91  Section 3.
For this, an azoline-mediated peptide backbone labeling strategy was used, which capitalizes on the hydrolytic lability of azolines. 113 Incorporation of the  18  O labels from BalhA into the liberated phosphate bolstered the proposed kinase-like mechanism, whereby heterocyclization occurs via direct activation of the peptide backbone. 112, 113 n contrast, TruD, a cyclodehydratase from the trunkamide (an azol(in)e-containing cyanobactin; see Section 3. 6) pathway, was reported to produce AMP and pyrophosphate (PPi) as byproducts when supplied with PatE2 (a precursor peptide from a related biosynthetic pathway), indicative of an adenylation mechanism. 114 The crystal structure of TruD (PDB: 4BS9) (Fig. 30A ) gave the rst insight into an azoline-forming cyclodehydratase, which was a dimer composed of three domains.
Domains 1 and 2 share structural homology with BalhC and MccB, an adenylase involved in microcin C biosynthesis (Section 4. 1. 3); however, TruD lacks the conserved ATP-binding loops seen in MccB. Domain 3 of TruD, which is homologous to BalhD, constituted a novel fold characterized by a large, negatively charged, shallow cle. Although not much information regarding substrate recognition and nucleotide binding could be obtained from the TruD crystal structure, biochemical data ruled out a kinase-type mechanism for TruD. 114 A nucleotidebound crystal structure of LynD (PDB: 4V1T) (Fig. 30B ), another cyanobactin cyclodehydratase, revealed that the aphosphate of the enzyme-bound ATP is obstructed from the peptide substrate, making the previously described adenylation mechanism less likely for heterocyclization.
Together, these data established that cyclodehydration proceeds via a kinase mechanism. Production of AMP and PPi as reaction byproducts has been proposed to occur as a result of a disproportionation or transphosphorylation reaction between P i and ADP catalyzed by the enzyme. 116  nucleotide-bound crystal structure was obtained for an orphan YcaO from E. coli (denoted as Ec-YcaO; PDB: 4Q86) (Fig. 31 ). 117 Although not yet rmly associated with a function, information obtained from the crystal structure of Ec-YcaO provided valuable insights into understanding the reactions catalyzed by YcaOs in RiPP biosynthesis. 8] [119]  Ala variants of the ATPbinding residues in BalhD predicted through sequence alignment with Ec-YcaO exhibited an increased K M for ATP and were veried to be vital for BalhD cyclodehydration activity in vitro, suggesting that ATP utilization is a universal feature of YcaOs.
117 9] [120] [121]  Structural alignment of cyanobactin cyclodehydratases TruD and PatD (azolineforming YcaOs) with Methanocaldococcus jannaschii YcaO (Mj-YcaO, thioamide-forming enzyme, PDB: 6PE3) revealed that the C-terminal carboxylate in TruD/PatD (and not Mj-YcaO) extends into the active site, possibly serving as a base that deprotonates the b-nucleophile of Thr/Ser/Cys. The C-terminal carboxylate is presumed to be kept in the extended conformation due to an abundance of Pro residues, oen found as a PxPxP motif, which is conserved among $90% of the bioinformatically identied azoline-forming YcaOs. 119 Indeed, alterations at the C-terminus of BalhD and McbD abolishes cyclodehydration activity. 117 hile certain YcaO proteins catalyze cyclodehydration, the E1-like partner protein serves as a potentiator and regulator of YcaO.
1. 1) known to interact  with the leader region of their corresponding precursor peptides. This wHTH motif, now recognized as the RiPP precursor recognition element (RRE), is a common feature employed by more than half of all known prokaryotic RiPP classes to engage their respective LPs (Section 4. 1. 1). 66 In addition to binding the RRE, Phe8 and Leu12 of the substrate McbA were shown to occupy two hydrophobic pockets in McbB1-dom1 and in the McbB1-dom1/McbB2-dom2 interface in the McbBCD synthetase complex (Section 4. 1. 1),  122 rationalizing the importance of an Fxxx(L/I/V) motif in the leader peptide of several LAP precursor peptides previously observed to be critical to bind to synthetases. 123 In certain LAP BGCs, such as the heterocycloanthracins (HCA), a divergent member of the E1-like superfamily, termed the F-protein (InterPro family: IPR022291), is responsible for substrate recognition.
125 The Balh pathway, however, tolerates non-cognate dehydrogenases that catalyze non-specic oxidation of azoles, as opposed to the microcin B17 pathway that strictly requires McbC. 125 Crystal structures of McbC bound to the microcin B17 product revealed that the precursor peptide is placed between the FMN cofactor and the conserved Lys-Tyr motif in the active site,  122  previously characterized to be important for BcerB and SaciB (distantly related azoline dehydrogenases) activity. 125 A mechanism for oxidation was proposed, which is supported by recent crystallographic data on the entire microcin B17 synthetase complex (PDB: 6GRI, Section 4. 1. 1). 122.
128 vaI, a TfuA-like protein (InterPro family: IPR012924) cooccurs with TvaH in all identied thioviridamide BGCs and has been proposed to support thioamidation, although its precise role remains undened. The characterization of additional thioviridamide-like compounds has revealed that the number of thioamides currently varies from three to ve, and identied further rare post-translational modications, such as Phe hydroxylation and reduction of the N-terminal pyruvyl moiety in thioalbamide. 11. 5. 1 Class-dening enzyme: thioamide-installing YcaO. Although no biochemical or structural data are currently available for thioamide-forming YcaOs from a bona de RiPP BGC, studies on non-RiPP YcaOs from methanogenic archaea have provided insights into their roles in thioamidation. Thioamideforming YcaOs, almost always encoded adjacent to TfuA, are ubiquitous in methanogens and have been proposed to install a conserved thioglycine residue (Gly465) in the a-subunit of methyl-coenzyme M reductase (McrA).