dataesr/scientific-paragraphs-categorization huggingface dataset:
(7) The sum of the exon size divided by 3 had to give us the protein size, which was inferred from the model obtained from the chromosomal sequence. The protein size could then be compared with the size of the query protein from Ensembl for size consistency. (8) Another consistency test was performed by determining whether the strands ("+" or "-") from the exons, which were deduced from the subject homologies, were all "+" or all "-. " Exons in alternating "+" and "-" strands for the same gene with homology to the same query protein would not make sense, and this result allowed us to diagnose cases of inconsistency. (9) We also confirmed the gene models that we obtained from the tBLASTn search of the Ensembl proteins with human DNA by comparing the hit coordinates with the exon coordinates available in the CCDS database, as annotated by Ensembl.
Genomic hits without counterparts in Ensembl proteins In cases where a genomic hit obtained by tBLASTn did not match the position of any human protein in the Ensembl list (Figure  1D ), it was considered as an indication that the human gene had not received a designation during the annotation process by Ensembl. The absence of an annotation was addressed by translating the homologous stretch of the human genome (subject) into amino acids and using the protein sequence for a homology search (BLASTp) with the nr section of GenBank (release 201. 0-April 2014). When a human homologous protein was found in nr, its complete sequence was compared (tBLASTn) with a DNA stretch of 20 kb around the initial L major hit with the human genome to find the gene model (if any) associated with this protein.
The particular case of functional specificity Considering the instances of enzymatic functional specificity between the 2 homologous proteins of L major and H sapiens in which the proteins were annotated as having differences in their enzymatic functionality (based on the assigned EC), we distinguished between the following categories (Figure  1E, F  and H ): (1) Uncertainty with the annotations occurred when at least one of the enzymatic functions in both proteins could not be confirmed (incomplete or unavailable EC). In these cases, we investigated the protein's name and function in UniProtKB/SwissProt  42  and attempted to verify whether the function described in this database matched that of TriTrypDB. If the function of the enzymes under comparison was synonymous in both organisms, the L major protein was diagnosed as a false positive for functional enzymatic specificity regarding its human counterpart; otherwise, functional specificity was assigned to the L major enzyme.
Protein domain mapping and secondary structure To better characterize whether ambiguous enzyme annotations (Figure  1G ) were derived from distant paralogous or analogous enzymes, we searched their catalytic cores by mapping the domain composition for the conserved regions of the H sapiens and L major homologous pairs using PROSITE, Pfam,  43  and the Conserved Domain Database  44  for homology comparison with identity and score rates of ~40% and ⩾120, respectively, and predicted their secondary structure (2D) profiles using PRALINE. 45.
Remote homology detection with hidden Markov models In addition to BLAST, we used HHpred (http://toolkit. tuebingen. mpg. de/hhpred)  46, 47 and HHsearch (http://mobyle. rpbs. univ-paris-diderot. fr/cgi-bin/portal. py),  48 hich implement hidden Markov models (HMMs) for a pairwise comparison of the profiles from sequence alignments in databases (Figure  1I ). HHpred detects the homologous sequences in humans with a higher sensitivity than BLAST. HHpred was performed with the default options, ie, local alignment and the scoring of secondary structure similarity, and HHsearch was executed with the Protein Data Bank (PDB; http://www. rcsb. org/pdb/home/home. do), HHblits (as the alignment generation method), 49 85% (as sequence coverage), 10 -6 (P value), and 10 (as maximal hit number). The sequences resulting from the first BLAST screening were further analyzed through HHpred and HHsearch to identify the possible remote sequence homologies in the human proteome that could result in false positives for the L major-specific enzymes.
Metabolic pathway significance To clarify the relevance of the putative enzyme targets of L major in terms of the metabolic impairment that results from their inactivation, we searched their respective EC in the KEGG pathway database (http://www. genome. jp/kegg/pathway. html). Then, we searched their metabolic pathway insertion to diagnose whether their inactivation may potentially affect L major without having deleterious consequences on human metabolism and, consequently, whether these enzymes can be used as targets for drug development (Figure  1J ).
From the complete genome sequences of B saltans (GenBank Assembly ID: GCA_001460835. 1, release ID: 2707578) and T borreli (http://www. sanger. ac. uk/resources/downloads/protozoa/trypanoplasma-borreli. html), we found the sequences encoding REL1 within the sequence NODE_50574 through a tBLASTn search of LmjF. 01. 0590 in the file Trypanoplasma_ borreli_contigs_20120411. fa. gz. We aligned the REL1 sequences of T brucei, T cruzi, L major, B saltans, and T borreli with ClustalW  56  and eliminated the column corresponding to gaps, and we searched the best phylogenetic relationship using maximum likelihood with MEGA7. 57 The substitution model was Jones-Taylor-Thornton, the rate among sites was considered uniform, and the tree inference was obtained by nearest neighbor interchange.
Classification challenges and annotation ambiguity In this study, we described a process for filtering out the falsepositive annotations of enzymatic specificity in the host-parasite b When a human EC was not available under "EC number not assigned," we gave the one available under "different EC numbers" (Table  3 ) following the pattern "different EC numbers"/"EC number not assigned. " c We applied the same pattern as in " b " for Ensembl accession numbers. d When an Ensembl protein is homologous to a putative functional specific enzyme of L major is available, their pairing relationship must be about homology; when such an Ensembl protein is not available, there is no homology and the pairing is only about enzymatic function (EC), ie, analogy. interactions released by AnEnPi. 32 The identification of specific protein targets in parasites (here, L major) compared with their host (here, H sapiens) is important for the development of drugs with the least amount of negative collateral effects for the host as possible.
When comparing the 2D alignments of these 9 homologous pairs, we only found slight differences, and it is difficult to claim that a drug for these L major targets would not have some kind of unwanted interaction with the human form that could result in negative side effects for the patients. The Ensembl database involves processes of automatic gene annotation that are eventually manually curated; this is also the case for Havana. 38, 58 The AnEnPi pipeline is completely automatic, and it classifies enzymes as specific, homolog, or analog according to their homology and.
Histoplasma capsulatum XP_001537255. 1 - - A Coccidioides immitis XP_001242243. 2, XP_001241281. 1 - - A Helminths Schistosoma mansoni - - - A Brugia malayi - - - A Loa loa - - - A Protozoan Toxoplasma gondii - - - A Plasmodium falciparum - - - A Trypanosoma cruzi X c X X X Trypanosoma brucei X X X X Leishmania donovani X X X X Leishmania braziliensis X X X X Giardia lamblia - XP_001705572. 1 - - Bacteria Staphylococcus aureus - - - - Streptococcus pyogenes - - - - Mycobacterium tuberculosis - A - A Abbreviation: EC, Enzyme Commission. a Accession number for homologous sequences. b A is for analogous sequences, when the homology could not be confirmed but the EC was annotated in kEGG. c X is for homologies among Tritryps; the details of these homologies if given in Table  S3. 1. enzymatic activities.
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is supported by fellowship from  Coordenação de Aperfeiçoamento de Pessoal de Nível Superior  (http:// www. capes. gov. br/) to L. C. C. , fellowship # 11917-13-0  from  Ciência sem Fronteiras  (http:// www. cienciasemfronteiras. gov. br/web/csf) to C. R. L. , Grant Universal  14/2013 #480866/2013-9  from  Ministério de Ciência e Tecnologia/Conselho Nacional de Desenvolvimento Científico e Tecnológico  to A. C. R. G. , and funding to  N. C. under  Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas  # 573642/2008-7. DEClARATIOn OF COnFlICTIng  InTERESTS: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
14. 0350 4. 2. 3. 1 Threonine synthase Hsa: NA/185875 -. -. -. - LmjF. 30. 1550 4. 2. 1. 70 Pseudouridylate synthase Hsa: NA/198331 -. -. -. - LmjF. 30. 0180 1. 1. 1. 60 2-hydroxy-3-oxopropionate reductase Hsa: NA/140632 -. -. -. - LmjF. 18. 1510, LmjF. 18. 1520 3. 6. 3. 6 H + -exporting ATPase Hsa: NA/123191 -. -. -. - Abbreviations: ATPase, adenosine triphosphatase; EC, Enzyme Commission; NA, not assigned; tRNA, transfer RNA. a kEGG accession numbers for L major. b kEGG accession numbers for Homo sapiens. c Ensembl accession numbers for H sapiens according to the format ENSG00000xxxxxx.
Data on OTSC use for non-variceal upper gastrointestinal bleeding (NVUGIB) in patients with cardiovascular comorbidities are currently limited. Patients and methods We prospectively collected and retrospectively analyzed our database from February 2009 to September 2015 from all patients who underwent emergency endoscopy for high-risk NVUGIB in 2 academic centers and were treated with OTSC as firstline (n = 81) or second-line therapy (n = 19). Results One hundred patients mean age 72 (range 27 -97 years) were included in this study. Fifty-one percent (n= 51) had severe cardiovascular co-morbidity (ischemic heart disease, congestive heart failure, hypertension, valvular heart disease, peripheral arterial occlusive disease and atrial fibrillation) and 73 % (n = 73) were on antiplatelet or/and anticoagulation therapy.
Patients and methods A total of 100 patients (mean age 72  [27 -97]  years, female 28 %, male 72 %) were treated between February 2009 and September 2015 at 2 academic medical centers (St. Bernward Hospital, Hildesheim, Germany; University Hospital of Strasbourg, France). For this observational 2-center study, data were collected prospectively and analysis was performed retrospectively. The cohort included patients after failure of a standard primary hemostatic method (injection, clip application or embolization) and lesions identified as high-risk, defined as lesion size ≥ 1 cm and visible vessel ≥ 0. 5 mm that were primarily treated with OTSC (▶ Table  1 ). All study procedures were performed at each center by 2 experienced endoscopists. In cases of active bleeding the OTSC was applied using a double-channel gastroscope (EG530 D, Fujifilm, Tokyo, Japan) in combination with an endoscopic water jet (Endo-Technik, Solingen, Germany).
Statistics Statistical analysis was performed using GraphPad Prism6 (GraphPad Software, Inc. , La Jolla, USA). Multiple linear regression with two independent variables was used for each pair of independent variables for correlation analysis. Correlations are described using Pearson correlation coefficient (r) and P value (P). For group comparisons, a t-test was used. A P value < 0. 05 was considered significant. We analysed patient data in order to determine if there was any correlation between patient/ bleeding characteristics and important treatment outcomes, such as success of therapy or mortality rates.
Statistical results Bleeding from duodenal lesions constituted the most frequent location in the study population (P < 0. 05). Both bleedingcaused and all-cause mortality had weak positive correlation with patient age (r = 0. 22, p = 0. 028 and r = 0. 21, P = 0. 028, respectively). Bleeding-caused mortality further positively correlated with Forrest Type Ia bleeding (r = 0. 37, P = 0. 0001). There was no positive correlation with other Forrest Types. We analyzed whether presence of renal disease alone or in combination with cardiovascular disease would affect mortality rate or surgical outcome. There was no significant difference for any of the parameters analyzed between different groups of patients, probably due to low numbers. We further analyzed the data according to presence/absence of cardiovascular disease (CVD) in patients.
Discussion In this prospective study, we evaluated the impact of NID on the accuracy of Doppler echocardiography to assess LVFP in patients with preserved LVEF at risk of developing abnormal exercise LVFP increase at low workload levels as the reflection of early stage HFpEF. We found that NID use had no influence on the association of septal E/e′ with LVEDP at rest. During exercise, the correlation between septal E/e′ and LVEDP persisted only if patients were on NID. These results may explain the conflicting data about the validity of stress E/e′ for the assessment of exercise LVFP in patients with preserved LVEF. This finding may have a clinical significance particularly when considering that NID are frequently withdrawn in routine practice before a stress test.
Limitations. Heart catheterization and trans-thoracic echocardiography were not performed at exactly the same time and this may have contributed to decrease the magnitude of correlations between LVEDP and E/e′. However, good quality echocardiographic exams are difficult to obtain in catheterization laboratories and can lead to acquisitions of poor quality. Moreover, this methodological choice ensured that echocardiographic acquisitions and analyses of the data were made blindly of invasive measurements. The patients were investigated using exactly the same exercise protocol and without any modification of their drug treatments. In patients treated with NID, treatment strategies were highly heterogeneous, with various doses and types of NID used, potentially leading to different effects on heart and vascular function.
Methods Study. This study was ancillary to the PREFFORT study (NCT01714752)  30. The study protocol and all methods applied were approved by the Committee for the Protection of Human Subjects of Pitié-Salpétière (Paris, France) and prior written informed consent was obtained from all subjects after being fully informed regarding the nature and risks of the study. We did the study in accordance with the principles of the international conference on harmonization guidelines on good clinical practice and the world medical association declaration of Helsinki. Patient selection. The methods was previously described in details elsewhere  30. Briefly, we prospectively enrolled 60 patients, among those admitted to the Pitié-Salpêtrière hospital in Paris, France, between 12/2012 and 07/2013, for clinically indicated left heart catheterization.
Clinical data. On admission, demographic data (age, sex, previous coronaropathy, diabetes, hypertension, other comorbid conditions), baseline clinical data, type of NID (non-dihydropyridine calcium channel blockers, beta-blockers) and of other current treatments were collected prospectively. The type and dose of NID were left at the discretion of the treating physician. Invasive hemodynamic assessment. After realization of the coronary angiography for diagnostic purpose, a fluid-filled pigtail catheter introduced through the radial artery was positioned in the mid-LV cavity using fluoroscopy, with the patient in the supine position. This catheter was connected to a strain-gauge pressure transducer positioned at right atrium level and zeroed before measurement. LV pressure tracings were recorded at baseline and during exercise.
Measurements were made off-line, blindly from echocardiographic and clinical data by two experienced physicians. LVEDP measurement was averaged over five cardiac cycles. A hemodynamic LV end-diastolic pressure (LVEDP) ≤16 mmHg was defined as normal at rest. An increase of LVEDP >16 mmHg (moderate), and to a further extent ≥25 mmHg (important), was considered abnormal during stress  1, 30, 31. Echocardiographic assessment. Transthoracic echocardiography was performed using a Vivid 9 (GE Healthcare; Horten, Norway) by an experienced physician blinded to clinical and invasive data. Images were transferred to a workstation equipped with the Echopac PC software version 12. 0 (GE Vingmed Ultrasound ® ; Horten, Norway). All examinations were analyzed off-line. All measurements were averaged over 3 to 6 cardiac cycles.
1 ). Continuous electrocardiographic monitoring was undertaken throughout the examination. The patient medications, including NID type and doses were unchanged between the invasive and non-invasive evaluations. Patients were asked at the end of the 50 Watts exercise if they had experienced dyspnea during the effort. Adequate mitral inflow, tissue Doppler signals and hemodynamic variables were obtained for all patients at baseline. E/e′ could not be measured accurately during exercise in two patients and hemodynamic data at exercise were missing in 4 patients, leaving 54 patients for final analysis.
Bound antibodies were detected using goat anti-mouse (dilution 1/3000, polyclonal 7076, Cell Signaling) or goat anti-rabbit peroxidase-conjugated antibody (dilution 1/ 3000, polyclonal 7074, Cell Signaling). Immunological complexes were revealed using ECL methods (Immobilon Western Chemiluminescence HRP substrate) and detected using an automatic medical X-ray processor (Kodak, Rochester, NY, USA). Bands densitometries were measured with the ImageJ software and normalized using β-actin as internal standard.
RANK-Dependent MZMs Provide a Niche for VSV Replication Since CD169 + MZMs have previously been shown to provide a restricted replicative niche for VSV  (Honke et al. , 2011) , we reasoned that loss of RANK-dependent MZMs could affect VSV replication. To test this hypothesis, we measured viral titers in spleens harvested from Tnfrsf11a DItgax and Tnfrsf11a f/f mice 7 hr after infection with VSV-OVA. There was a significant reduction in splenic VSV titers from Tnfrsf11a DItgax mice compared to littermate controls (Figure  4A ), which correlated with reduced expression of virus-encoded OVA, determined by qRT-PCR with RNA isolated from total splenocytes (Figure  4B ). These data showed that RANK signaling in CD11c-expressing cells promotes early viral replication and expression of viral antigens in the spleen.
To confirm the restricted replication of VSV in CD169 + cells in situ, we used a recombinant strain of VSV expressing GFP (VSV-GFP) and performed confocal microscopy (G-I) Shown in (G): experimental strategy for the adoptive transfer of mCTLs. CD45. 1 + mice were immunized with Lm-OVA; 3 weeks later, CD4 and CD8 T cells were isolated from spleen and adoptively transferred to cohorts of naive Tnfrsf11a f/f and Tnfrsf11a DItgax mice. A further 7 weeks after T cell transfer, mice were infected with VSV-OVA (H) or Lm-OVA (I); activation of adoptively transferred mCTLs (CD44 + , CD45. 1 + ) and priming of endogenous naive CD8 T cells (CD45. 2 + ) were measured simultaneously in spleen 5 days after challenge as expansion of Tet + cells. Data are represented as mean ± SEM, and statistical analysis was performed with the Mann-Whitney test; **p < 0.
To track the mobilization of mCTLs, we adoptively transferred OVA-specific CD8 T cells from OT-I-GFP mice; 2 months after immunization with Lm-OVA, Tnfrsf11a f/f and Tnfrsf11a DItgax mice that had received OT-I-GFP cells were infected with VSV-OVA, and the spleens were harvested after 7 hr. We performed confocal microscopy on spleen sections to localize OT1-GFP cells. Mobilization of memory OT-I-GFP cells to the splenic MZ and interfollicular regions could clearly be seen upon VSV-OVA challenge of immunized mice (Figure  6E ). Furthermore, as expected, the recruitment of GFP-expressing OT-I cells was reduced significantly in Tnfrsf11a DItgax mice, which correlated with the impaired induction of IFNg and CXCL9 expression (Figure  6B ). These data demonstrate that DC-mediated triggering of mCTLs during secondary infection is RANK dependent.
We found no defects in B cell homeostasis after deletion of RANK expression in CD11c + cells (data not shown), indicating that the role of RANK in the maintenance of CD169 + MZM is complementary to B cell-derived LT. (F) Wild-type mice were immunized with Lm-OVA and, 4 months later, challenged i. v. with wild-type VSV and administration i. p. of either OVA-conjugated anti-DEC205, anti-DCIR2, or isotype-control antibody. Five days later, endogenous OVA-specific mCTL (CD44 + Tet + ) expansion was measured in spleen by flow cytometry. (G) Lm-OVA-immunized Tnfrsf11a f/f and Tnfrsf11a DItgax mice were challenged with wild-type VSV with OVA-conjugated anti-DEC205 or isotype-control antibody; mCTL expansion was measured in spleen after 5 days. Graphs represent mean ± SEM of n = 2-6 for isotype control and n = 5-7 for the other groups.
Immunofluorescence Microscopy Mice were killed 7 hr post-infection, and spleen was harvested and fixed for 4 hr in Antigenfix (DiaPath, MM France) at 4 C, washed in phosphate buffer  (GIBCO, ref. 14190-094)  for 1 hr, dehydrated in 30% sucrose overnight at 4 C, and embedded in optimum cutting temperature medium (OCT) freezing media  ref. 4583). Spleen sections were blocked for 1 hr in 2% BSA before incubation with primary antibodies for at least 1 hr or overnight, depending on the antibodies. Stained spleen sections were then mounted in ProLong Gold antifade reagent with DAPI (Life Technologies, ref. P36931) and analyzed by confocal microscopy using the Zeiss LSM 780. Quantification of colored pixels was performed using ImageJ software. OT-I cell clustering was defined as a group of 3 or more proximate cells.
The proportion of clustered cells was quantified according to the total number of OT-I GFP cells present on the whole section. The limits of the MZ region were determined with nuclear density and RANKL expression by MRCs lining the MZ. Staining was quantified only in the MZ by manual separation using ROI Manager tools in ImageJ. The same regions from each section were applied to all channels after specification of the limit threshold intensity for each channel. The mean gray value for all channels was measured using the ROI Manager tool. Statistical Analysis p values were calculated using either the Mann-Whitney test or the Fisher test, where appropriate, using GraphPad prism software. p values are indicated as: *p < 0. 05; **p < 0. 01; ***p < 0. 001; and ****p < 0. 0001. A-B ) CD45. 1 + mice were immunized with Lm-OVA, 3 weeks later CD4 and CD8 T cells were isolated from spleen and adoptively transferred to cohorts of naïve Tnfrsf11a f/f and Tnfrsf11a ΔItgax mice, a further 7 weeks after T cell transfer mice were infected with VSV-OVA (A) or Lm-OVA (B); IFNγ and GrzB expression in adoptively transferred mCTL (CD44 + , CD45.
(G-I) Shown in (G): experimental strategy for the adoptive transfer of mCTLs. CD45. 1 + mice were immunized with Lm-OVA; 3 weeks later, CD4 and CD8 T cells were isolated from spleen and adoptively transferred to cohorts of naive Tnfrsf11a f/f and Tnfrsf11a DItgax mice. A further 7 weeks after T cell transfer, mice were infected with VSV-OVA (H) or Lm-OVA (I); activation of adoptively transferred mCTLs (CD44 + , CD45. 1 + ) and priming of endogenous naive CD8 T cells (CD45. 2 + ) were measured simultaneously in spleen 5 days after challenge as expansion of Tet + cells. Data are represented as mean ± SEM, and statistical analysis was performed with the Mann-Whitney test; **p < 0. 01.
supported by grants to T. L. from L' Agence Nationale de la Recherche (ANR)  ( ANR-09-MIEN-029-01  and  ANR-10-BLAN-1302-01 ); the  European Research Council , FP7/2007-2013 grant agreement number  260753 ; and institutional funding from  Inserm ,  CNRS , and  Aix-Marseille-Universite. Microscopy  facilities are supported by  ANR-10-INBS-04-01  ( France-BioImaging ).