dataesr/scientific-paragraphs-categorization huggingface dataset:
Importantly, the AF predicted interface of the RAD18 RING and SAP domains is compatible with the RING-RAD6 interface, as deduced from a model created based on the crystal structure of a closely related RING-E2 (PDB:6W9A) structure (Figure  S8C ). The SAP-RING dimer is also compatible with the previously determined crystal structure (PDB:2Y43) of the dimeric RAD18 RING domain (Figure  S8D )  (11). We have modelled the RING and SAP domain from the same RAD18 monomer as interacting, however, it is entirely feasible that the RAD18 dimer adopts a conformation in which the RING and SAP domains from different monomers interact. The predicted interface of RING and SAP includes two salt bridges; one between R51 of RING and D290 of SAP, and another between E69 of RING and K245 of SAP (Figure  3C ). A hydrophobic interaction network composed of residues A287, M284 of SAP and L48 of the RING domain further strengthens the RING-SAP interaction (Figure  3C ).
For the acquisition of all spectra, 3D transverse relaxation optimized spectroscopy (TROSY) pulse sequences with 2 H-decoupling (HNCO, HNCA, HN(CO)CA, CBCA(CO)NH, HNCACB, HN(CA)CO and HN(CO)CACB)  (62) (63) (64)  and apodization weighted sampling were used  (65). The resulting spectra were processed using NMRPipe (66) and assigned with the program Cara  (67). Seventy-five percent of all amides were assigned for the free MAGEA4-MHD and seventy percent for the complex with RAD18 R6BD peptide. Backbone assignments of the MAGEA4-MHD domain alone and of the complex have been deposited in the Biological Magnetic Resonance Bank (BMRB) under accession codes 51823 and 51822 respectively. For NMR-based interactions studies, the 2 H, 13 C, 15 N labelled free MAGEA4-MHD sample from backbone assignments was titrated with 3.
ITC experiments A 27 amino acid peptide containing amino acids 340-366 of RAD18 was purchased from GenScript and used at 200 µM for ITC binding experiments. Full length MAGEA4 WT, MAGEA4 M161D, MAGEA4 triple (M161D, I205D and L288D) and RAD6 WT were purified as described in the previous section and concentrated to 20 µM. The ITC experiments were performed using a MicroCal ITC200 (Malvern), with a sample volume of 350 µL and a ligand volume of 75 µL. All experiments were performed at 25 °C and reference power 5. The initial injection volume was 1 µL and all subsequent injections were 2. 5 µL at 3 minute intervals. All experiments were performed in SEC buffer. Data baseline subtraction, analysis and dissociation constant determination were conducted using Microcal PEAQ-ITC Analysis Software (Malvern).
Full mass scans were acquired for a mass range 350-1700 m/z in profile mode in the orbitrap with resolution of 120000. The AGC target was set to Standard and the injection time mode was set to Auto. The instrument was operated in data dependent acquisition (DDA) mode with a cycle time of 3 sec between master scans and MSMS scans were acquired in the Orbitrap with a resolution of 30000, with a fill time of up to 100 ms and a limitation of 2e5 ions (AGC target). A normalized collision energy of 32 (34 for diGLY) was applied. MS2 data was acquired in profile mode. The DiGly samples were processed in the same way with few exceptions, as noted above.
MS data analysis -MSFragger All raw files were converted to mzmL format using MSConvert from Proteowizard59, using peak picking from the vendor algorithm. Files were then searched using MSFragger v3. 7  (78)  in Fragpipe v19. 1 against the Swissprot Homo sapiens database (20,594 entries) containing common contaminants and reversed sequences. The standard settings of the Fragpipe TMT10 workflow were used. The following modifications were included into the search parameters: Carbamidomethyl (C) and TMT10 (K) (fixed modification), Acetyl (Protein N-term), Oxidation (M) and TMT10 (N-term) (variable modifications). For the full scan (MS1) a mass error tolerance of 10 ppm and for MS/MS (MS2) spectra of 0. 02 Da was set. Further parameters were set: Trypsin as protease with an allowance of maximum two missed cleavages and a minimum peptide length of seven amino acids was required.
Mass photometry Mass photometry experiments were performed using a OneMP Mass Photometer (Refeyn). Experiments were performed in SEC buffer. Mass calibrations were conducted with NativeMark TM Protein Std (Invitrogen) diluted in SEC buffer in a 1 in 400 dilution. Data was collected using AcquireMP (Refeyn) and analysis was performed using DiscoverMP (Refeyn). For the RAD18/RAD6/MAGEA4 complex, the sample was first cross-linked with BS3 cross-linker, followed by loading on a S200 3. 2/300 analytical column to separate out the cross-linked complex from the uncross-linked proteins. The peak fraction was selected for MP analysis.
Acknowledgements: We thank the  EMBL Mass spectrometry core facility , especially  Jennifer Jasmin Schwarz  and  Frank Stein  for the data acquisition and analysis,  Martin Pelosse  for training and maintenance of the EMBL eukaryotic expression facility,  Caroline Mas  for training and access to the biophysics platform. We thank  Aline Le Roy  and  Christine Ebel , for assistance and/or access to the Analytical Ultracentrifugation (AUC) platform. This work used the platforms of the Grenoble Instruct-ERIC center (ISBG; UAR 3518  CNRS-CEA-UGA-EMBL ) within the  Grenoble Partnership for Structural Biology (PSB ), supported by  FRISBI  ( ANR-10-INBS-0005-02 ) and  GRAL , financed within the  University Grenoble Alpes graduate school (Écoles Universitaires de Recherche)   CBH-EUR-GS  ( ANR-17-EURE-0003 ).
4. 0. 3524 (72). Parameters were set as follows: Trypsin (K/R only), charge states 4-8, peptide length 7-50, percent Evalue threshold = 50, MS mass tolerance = 10 ppm, MS/MS mass tolerance = 10, elution width = 0. 5 min. BS3 cross-links residue pairs were constrained to K on one end and one of KSTY on the other. Identifications were manually validated, and cross-links with an E-value corresponding to <0. 05% FDR were rejected. The data export from the Studio was filtered to retain only cross-links with a unique pair of peptide sequences and a unique set of potential residue sites. For DiGly analysis, the raw data was processed with IsobarQuant (73) and as search engine Mascot (v2. 2. 07) was used. Data was searched against the Uniprot Escherichia coli database (UP000000625, 4518 entries, including common contaminants and reverse hits, May 2016) with the amino acid sequences of interest added (His-tagged RAD18, His-tagged E1, USP46, RAD6, His-tagged MAGEA4, UBB, UBC, UBD, RL40 and RS27A, all from homo sapiens).
4 kV. The capillary temperature was set at 275°C. Full mass scan was acquired with mass range 375-1500 m/z in profile mode in the orbitrap with resolution of 120000. The filling time was set at maximum of 50 ms with a limitation of 4x105 ions. Data dependent acquisition (DDA) was performed with the resolution of the Orbitrap set to 30000, with a fill time of 94 ms and a limitation of 1x105 ions. A normalized collision energy of 38 was applied. MS2 data was acquired in profile mode.
Conventional SCIG (cSCIG) requires frequent infusions (daily, weekly, or biweekly) and volume limitations often necessitate administration into multiple sites  [2, 4]. Facilitated subcutaneous immunoglobulin (fSCIG) is a dual-vial unit of recombinant human hyaluronidase (rHuPH20) and 10% human normal immunoglobulin G (IgG)  [5, 6]. rHuPH20 depolymerizes hyaluronan, increasing subcutaneous tissue permeability and allowing infusion of larger volumes of IgG compared to cSCIG. As a result, fSCIG can be self-administered at home every 3 to 4 weeks using a single infusion site  [5, 6]. Although data on efficacy and safety of fSCIG in SID are limited  [7] , a pivotal phase 3 study of patients aged 4-78 years with PID (NCT00814320) demonstrated that fSCIG was effective and bioequivalent to IVIG at the same administration intervals, with fewer systemic reactions  [8].
Patients and Study Design FIGARO was a prospective, observational, phase 4 study conducted in 14 centers in 6 European countries: Czech Republic, Germany, Greece, Italy, Poland, and Spain. Study initiation was December 2016; database closure was August 2021. Duration of follow-up was dependent on when the patient was included during the study period. Patients were followed for up to 36 months. Patients were eligible to enroll if they had received at least one fSCIG infusion for PID or SID or were due to receive one and met the following criteria: indication for IGRT, available for long-term follow-up, and provided informed consent. Note that due to center selection, there was likely a bias towards enrolment of a higher number of patients with PID versus those with SID. The primary objective was to assess drug utilization patterns including dose, treatment interval, infusion volume, infusion sites, infusion rate, needle size, site of care, type of pump, and caregiver support.
Assessments Data were collected from patient charts, diaries, and patient interviews and entered into an online form at regular intervals. Centers were required to perform complete data entries one to four times per year. Data were collected on parameters, including patient demographics, clinical characteristics, and IGRT treatment history. Physician interpretation of serum IgG trough levels was evaluated using a rating scale of "too low," "satisfactory," "optimal," or "too high. " Infections, including acute severe bacterial infection (ASBI) events and ADRs (categorized as local or systemic) were also evaluated. Healthcare utilization was assessed by recording number of training sessions, nurse visits, patient visits, hospitalizations and rehabilitations, and sickness days.
The most frequently reported infections were sinusitis (39/159 events [24. 5%]; PID: 32/132 [24. 2%] events, SID: 7/27 [25. 9%] events), bronchitis (23/159 events [14. 5%]; PID: 23/132 [17. 4%] events), and pharyngitis (9/159 events [5. 7%]; PID: 8/132 [6. 1%] events, SID: 1/27 [3. 7%] event). At 6, 12, 18, 24, 30, and 36 months, other bacterial infection events were reported in 34/134 (25. 4%), 36/128 (28. 1%), 13/70 (18. 6%), 16/55 (29. 1%), 11/57 (19. 3%), and 9/46 (19. 6%) patients, respectively. Overall, the rate of other bacterial infections at 36 months was higher in the PID cohort (22. 9%) than in the SID cohort (9. 1%). At follow-up, hospitalization was required in 4/43 other bacterial infection events (9. 3%; PID: inguinal abscess: 1 day in hospital; gastroenteritis: 4 days in hospital; COVID-19: 7 days in hospital; and upper respiratory tract infection: 2 days in hospital) at 6 months (hospitalization data unknown for 2 events), 2/45 events (4.
4%; PID: bacterial infection: 3 days in hospital; SID: appendicitis: 10 days in hospital) at 12 months (hospitalization data unknown for 1 event), 1/15 events (6. 7%; PID: diarrhea: 19 days in hospital) at 18 months (hospitalization data unknown for 3 events), and 1/22 events (4. 5%; cholangitis: 7 days in hospital) at 24 months (hospitalization data unknown for 1 event). No hospitalizations were documented at 30 and 36 months for other bacterial infection events.
Acknowledgements The authors thank the patients who participated in this trial, any caregivers, and study-site personnel. The authors also wish to thank the investigators and study nurses: Aleksandra Matyja-Bednarczyk ,  Prof. Ulrich Baumann ,  MHH Hanover ,  Aleksandra Pyzik ,  Anna Hedwig Müller ,  Britta Dölle ,  Eileen-Julya Hempel ,  Eva Spatz ,  Evangelia Farmaki ,  Ewelina Grywalska ,  Inga Groschek ,  Laura Ruiz López ,  Magdalena Celińska-Löwenhoff ,  Margarethe Platz ,  Pavlina Kralickova. Medical writing services were provided by  Jane Kondejewski, PhD  of  SNELL Medical Communication Inc. and funded by  Takeda Pharmaceuticals International AG.
Under fertilization conditions, the mutant oocytes do not enter into an embryonic development process. Furthermore, we conducted a comparative proteome analysis of wild type and Exosc10 knockout mouse ovaries, and identified EXOSC10-dependent proteins involved in many biological processes, such as meiotic cell cycle progression and oocyte maturation. Our results unambiguously demonstrate an essential role for EXOSC10 in oogenesis and may serve as a model for primary ovarian insufficiency in humans. Data are available via ProteomeXchange with identifier PXD039417.
Follicle count Ovaries were serially sectioned at 5 μm using a microtome (Shandon, Pittsburgh, PA, USA). One out of 5 sections were mounted on glass slides to avoid counting the same follicle several times, dried, rehydrated and stained with hematoxylin and eosin. A minimum of 3 ovaries have been counted for each group and age. Follicle stage was determined using the Pedersen's classification  [14]. A follicle was counted only if a healthy oocyte nucleus was visible in order to avoid recording atretic oocytes. Follicles were counted on at least 10 sections per ovary and the percentage of each follicular stage regarding the total number of follicles was represented. Histological sections were analyzed using a NanoZoomer 2. 0-RS (Hamamatsu Photonics, Hamamatsu, Japan) and the NDP. view2 viewing software (Hamamatsu Photonics).
Protein digestion, Mass spectrometry acquisition and Protein identification and differential quantification Proteins (2 µg) were in-gel digested with 12. 5 ng/μL sequencing grade modified trypsin (Promega, Charbonnières-les-Bains, France) after concentration on one band using a 4-12% Bis-Tris precast gel (NuPAGE ™ ) as previously described  [15]. The resulting peptide mixtures were injected onto a TimsTOF Pro instrument (Bruker Daltonik GmbH, Bremen, Germany) coupled to a NanoElute HPLC System equipped with on a 75 µm × 250 mm IonOpticks Aurora 2 C18 column (Ion Opticks Pty Ltd, Fitzroy, Australia) and LC-MS/MS data were acquired using the PASEF method as previously described  [16]. MS data were processed with the Data Analysis 5. 1 software and peptide and protein identification were performed using the Mascot (Mascot server v2.
5. 01; http://www. matrixscience. com) database search engine and its automatic decoy database search to calculate a false discovery rate (FDR). MS/MS spectra were queried against the Mus musculus UniProt KB proteome database (release UP000000589; 21959 sequences) and a common contaminant database such as trypsin, keratins, BSA, from the Max Planck Institute of Biochemistry, available in Mascot (247 sequences). Mass tolerance for MS and MS/MS was set at 15 ppm and 0. 05 Da. The enzyme selectivity was set to full trypsin with one miscleavage allowed. Protein modifications were fixed carbamidomethylation of cysteines, variable oxidation of methionine. Identification results from Mascot (. dat files) were imported into the Proline Studio software  [17]. This software was then used to validate protein identification with a peptide rank = 1, a peptide score > 30 and a 1% FDR at the peptide spectrum matches level.
Proteomic data analysis Differentially detected protein list was imported into Cytoscape  [20]  3. 8. 2 by using Stringapp 1. 7 for visualizing molecular interaction networks and biological pathways with expression data. According to label-free data, fill color of nodes was set by a continuous mapping : log Ratio (FC) < 0 in blue and log Ratio (FC) > 0 in red. Proteins with a log2 ratio > 1 are considered as up-regulated in Exosc10 cKO(Gdf9) and with a log2 ratio < -1 are considered as down-regulated in Exosc10 cKO(Gdf9) ovaries. Transcriptomics data downloaded from https://www. ncbi. nlm. nih. gov/geo/query/acc. cgi?acc=GSE141190; (Wu and Dean, 2020) (ARN polyA only, and stage GV; 7 controls and 15 Exosc10 oocyte-specific knockout) were submitted to the R package DESeq2  [21]. Data were added to be visualized by a data table import into Cystoscape.
Quantitative PCR analysis RNA extractions were performed using the RNeasy Plus Micro Kit (Qiagen, Hamburg, Germany) and integrity of the different RNA (9 < RIN < 9,6) was tested with 2100 Bioanalyzer instrument (Agilent, Santa Clara, CA, USA). Reverse transcription was performed using iScript cDNA synthesis Kit (Bio-Rad) and the quantitative PCR using the iTaq Universal SYBR Green Supermix (Bio-Rad). The normalized relative expression for each target gene (ΔΔCq) and statistical analyses were performed with CFX Maestro software (Bio-Rad v 2. 2. ). Gene expression was measured between Exosc10 +/f and Exosc10 cKO(Gdf9) biological groups, each containing six biological replicates and two technical replicates. Rplp0 and Rpl13a are used as reference genes. Primer sequences are listed in Table  S1.
We first confirmed that, as expected, EXOSC10 expression is decreased in mutant ovaries (Table  S2 ). Using Cytoscape software, we displayed exclusively the proteins included in a network (Fig. 5A ). To establish a link between RNA and protein expression, the single cell RNA profiling data from Wu and Dean  [11]  was integrated in the graphic display presented in Fig. 5A. Among these entities, 40 % show consistent data in proteomic and transcriptomic analyses. Forty five percent show opposite RNA and protein expression profiles. This discrepancy could be explained by a difference in the design of our experiments (whole ovary for the proteomic experiment versus isolated oocytes for the RNA-Seq data). We identify sub-networks and pathways impaired by Exosc10 invalidation in the oocytes that are comprised of proteins known to have essential roles in oocyte maturation and early embryogenesis.
Pooled ARR and gadolinium-enhancing lesion data show rate reductions of 53. 9% (p\0. 001) and 95. 9% (p\0. 001), respectively, with ofatumumab versus teriflunomide treatment for ASCLEPIOS I/II (see Fig. S1 ). AEs and AE rates were similar with ofatumumab versus teriflunomide treatment, including infections overall and malignancies (see Table  2 ). One case of myocardial infarction was also noted in the ofatumumab group. The efficacy and safety of ofatumumab versus teriflunomide for first-line use in early RMS patients was also evaluated in ASCLEPIOS I/II on the basis of a protocol-defined cohort of 615  recently diagnosed and treatment-naı ¨ve RMS patients. Consistent with the overall ASCLE-PIOS population, these early RMS patients achieved significantly higher levels of disease control (reductions in relapse rate, MRI activity, and risk of disability worsening) when treated with ofatumumab compared with teriflunomide.
5 at baseline to 0. 1 by Week 12, while the proportion of patients free of these lesions was 64. 2% at baseline and 94. 1% by Week 12  [17]. Concurrently, the APOLITOS study in RMS patients from Japan and Russia demonstrated the superior efficacy of ofatumumab versus placebo on new brain lesion activity at 24 weeks, with a 100% reduction in the number of gadolinium-enhancing T1 lesions from baseline by Week 48 with ofatumumab treatment  [42]. These studies provided further evidence of the benefits of ofatumumab 20-mg SC and confirmed the consistency of effects across ethnic groups. Long-term safety and benefits of ofatumumab 20-mg SC are being evaluated in the ongoing ALITHIOS extension study, which consists of patients who completed the ASCLE-PIOS I/II, APLIOS or APOLITOS trials. Interim data have shown the long-term benefits and safety, and continued positive benefit-risk profile, of ofatumumab 20-mg SC treatment up to 4 years (core studies and extension) in patients with RMS  [43].
ACKNOWLEDGEMENTS The authors thank the participants of the studies referenced in this article. Funding. Sponsorship for this study and  Rapid Service  Fee were funded by  Novartis Pharma AG. Medical Writing, Editorial, and Other Assistance. Writing assistance in the preparation of this article was provided by  Brianna Fitzmaurice  of  Novartis Ireland Ltd. Support for this assistance was funded by  Novartis Pharma AG. The authors would also like to thank  Miriam King  of  Novartis Pharma AG  for her contributions in organizing the production of this article. Author Contributions. The conceptualization of this article was carried out by  Goeril Karlsson ,  Roseanne Sullivan ,  Gordon Graham  and  Stephen Hauser. Roseanne Sullivan ,  Gordon Graham , and  Dieter A. Ha ¨ring  assisted with the literature search.
An ADDobody library has been generated in a format suitable for ribosome display and is actively being employed in selections to generate high-affinity binders against purified PLA2s, disintegrins, and hyaluronidase. Initial rounds of ribosome display, using the ADDobody library, have already yielded results against the aforementioned targets, especially PLA2s and hyaluronidase. In addition, a naïve nanobody library has also been generated (by Dr Huan Sun and Dr Johara Stringari). Main Conclusions-The primary goal of the ADDovenom project is to combat snakebite envenomation by producing safe, effective, and affordable antivenoms. The preliminary data indicate that ribosome display is an effective methodology for accomplishing this objective by generating high-affinity binders against an assortment of pertinent snake venom targets.
toxins is a serious concern for public health, the evaluation and characterisation of their risk are priorities for the European Food Safety Authority (EFSA), which also encourages the search for occurrence data and the development of reliable and efficient analytical methods. Among the different methods, electrochemical cell-based biosensors are a promising strategy. They are based on cell-based assays, which measure the toxicological effect of toxins on cells and provide an estimation of the composite toxicity of a sample, and have the added advantage of the high sensitivity provided by electrochemical detection techniques. With this aim, Neuro-2a cells were immobilised on electrodes of different materials, and their viability was assessed using a tetrazolium salt. After optimisation of the assay conditions, the effect of CTX and TTX standard solutions on the immobilised cells was evaluated.
Although there are rarely fatal cases, snakebites are medically important in Albania, mainly in the summer season when the fieldwork is carried out during the feeding time of the vipers, out of the midday high temperatures. Therefore, this retrospective study will highlight the importance of snakebite envenoming and raise awareness to prevent their morbidity. The description of the 47 snakebites case studies over a decade, from the villages of Fier County, hospitalized in the regional hospital, is presented. Detailed data on the localities, age, gender, bitten location, supportive treatment, bite date, and hospitalized time, are analyzed. The snakebites were during the seasonal fieldwork, from March to November. Snakes were identified as Vipera sp. , or simply as snakebite. The hospitalized patients from the snakebites were all farmers from the agricultural areas in Western Lowland.
Acknowledgements: We thank the  NRBC-E Program  ( MULTITOX  project), the  INTER-REG Atlantic Area  ( ALERTOX-NET  project), the  LABEX LERMIT  ( DETECTNEUROTOX  project) and the  GDR PHYCOTOX. Keywords: cyclic imine; lateral flow test; nicotinic acetylcholine receptor Acknowledgements. This study was supported in part by the project  ANTIBOTAB  funded by the  European Union , and in part by the  CNRS  and the  Institut Pasteur of Paris. We thank  Mrs. Patricia Villeneuve  for essential help with the logistics and maintenance of animals at the CNRS animal house facility in Gif-sur-Yvette. induction of catalase activity has been demonstrated. The latter constitutes a means of cellular defense against the presence of paracetamol at the level of two target organs. Keywords: bioaccumulator; Helix aspersa; paracetamol; toxicity.