dataesr/scientific-paragraphs-categorization huggingface dataset:
tuberculosis isolates and estimated the recent TB transmission rate in Nigeria. This study was followed by Molina-Moya et al. [6] , in which spoligotyping results have been produced in 36 states, from Ziehl-Neelsen stained sputum smears on more than 500 isolates. Results are in line with the previous study, namely: an over-representation of L4. 6. 2 throughout the country (half of the patterns), with an over-representation even becoming a majority of L5 in the southeast; a presence, finally, of L6 in the northwest, northeast, and west  [6]. However, only two sequencing projects, namely PRJNA725394, and PRJEB15857, followed these spoligotype-based studies, leading to a limited amount of only 31 genomes available for Nigeria on the NCBI  [7]. The summary of the first bioproject, which focuses on southwestern Nigeria, concludes that L4.
6. 2 is very prevalent in this region. The second bioproject stressed that Nigeria has an emerging problem of multidrug-resistant isolates (especially rifampin), and that some L2 isolates have become XDR-TB  [8]. To sum up, L4. 6. 2, L5 and L6 lineages from these bioprojects have not been specifically studied in-depth. We should also mention PRJNA604127, which focuses on the presence of M. bovis. Alltogether the amount of data, as compared to the bulk of the 160,000 genomes available on the NCBI, is limited for a population of more than 200 Millions inhabitants. This justifies the launch of new WGS studies in Nigeria, in particular on L5 and L6, which could account for up to 10 to 20 percent of total TB cases in West-Africa  [9]. Using WGS, we can now go much deeper into our understanding of MTBC genomic diversity and phylogenetic reconstruction using new bioinformatic pipelines.
Patients and isolates data collection The data used in this study are of two types: those already existing on NCBI, and the acquisition of a new dataset on site. At the NCBI level, we investigated the references produced in the search engine of the main portal by putting the keyword "Tuberculosis" and "Nigeria". Specifically, we looked at results from Pubmed, and the bioproject and Sequence Read Archive (SRA) databases. Similar work was done on neighboring countries for comparison, replacing "Nigeria" in the query with "Benin", "Togo", "Chad", "Niger", "Cameroon", and "Ghana". Concerning the new data, it consists on a set of 325 patients, among which a cohort of 165 patients from the AKTH (Aminu Kano Teaching Hospital) regional lab comprised complete clinical histories from six Nigerian states, namely: Borno (5), Jigawa  (5) , Kano (98), Katsina  (19) , Kebbi  (25)  and Yobe (2), while 8 archive DNA of Nigerian origin from two previously published studies were added and three isolates from France were also included (Fig  1 ).
Patient information have been collected concerning the gender (for 157 patients), age, HIV status, and concerning the place of living: urban, semi-urban, semi-rural or rural (Table  1 ). At the disease level, we noted whether it was pulmonary TB or not, whether it was a new case or a retreatment case, and we also collected data on drug-resistance assessed by phenotypic drug susceptibility testing (pDST). The antibiotic susceptibility has been evaluated for the following drugs: Isoniazid (INH), Ethambutol (EMB), Rifampicin (RIF), Streptomycin (STR), Pyrazinamide (PZA), Fluoroquinolones (FQ), Amikacin (AMK), Ethionamide (ETH), Para-aminosalicylic acid (PAS), Linezolid (LZD), Kanamycin (KAN), Capreomycin (CPR), and Prothionamide (PTO). pDST was done in the Regional TB reference laboratory in Kano using a classical proportion method  [14].
Other genomic data collection Variant calling of the fastq data has been performed using TB-Annotator (91,465 isolates version,  [16] ), after integration of the newly sequenced isolates in the database. Lineage attribution has been done by using the robust SNP barcode for typing Mycobacterium tuberculosis complex isolates of Coll et al. [4] , as developed in the TB-Annotator platform. Sublineage information from the Coscolla et al. scheme  [1]  has been applied to isolates of Lineages 5 and 6, and it has been compared to the new proposal for L5 taxonomy published in  [13]. DNA alignments of SNPs have been extracted for the following datasets: • All L5 isolates from TB-Annotator, encompassing the new sequenced ones; • All M. bovis isolates from TB-Annotator, encompassing the Nigeria ones, thanks to the selection based on the NC 000962.
A potentially noisy but scalable version of the spoligotypes was obtained by aligning the reads to the 43 reference spacers with BWA  [20]. Each variant indexed in the database is annotated for resistance based on TBDB data  [21]  and WHO data  [22]. These spoligotypes and resistance extractions are done by TB-Annotator too. A list of mutations potentially interesting for the study of antibiotic resistance was then produced from the SNP matrix of the considered isolates (in row, the isolates, in column the mutations) and by considering for Y each resistance vector associated to each antibiotic. We then extracted the list of columns closest to the target Y in the sense of the Matthews correlation coefficient  [23].
Bioinformatical analysis and statistics In addition to the newly sequenced isolates and the previously mentioned bioprojects, the NCBI search recovered 48 isolates from Nigeria from the multi-country generalist project PRJEB50999 and two isolates from PRJNA825524, bringing the total to 101 isolates (plus 15 M. bovis from PRJNA604127). It should be noted that there is an additional three L5 isolates from Nigeria in  [24] , but these are PacBio data that our pipeline does not currently process. The search for isolates for neighboring countries has been relatively successful depending on the country. We found only one strain from Benin, an L5, which was not included in the TB-Annotator due to a quality problem. Also, surprisingly, no sequenced genomes from Togo, Chad, or Niger were available on NCBI prior to this study.
However, we were able to integrate an isolate from our laboratory for Benin (since published under the accession SRR22419692), a second for Niger (SRR22419698, from the same bioproject PRJNA905483), and a final one for Togo for comparison. The PRJEB40777 project allowed us to integrate 201 representative isolates from Cameroon, and the PRJNA616081 project allowed us to do the same with 175 isolates from Ghana, see also S1 Material for further information on patients from Nigeria and S2 Material for SRAs references and origins. Principal component analysis was performed using the PCA function of the scikit-learn python library. The data matrix provided had as many rows as patients in the study, and as many columns as antibiotics. The data was standardised and slightly noisy (Gaussian noise, mean zero, standard deviation 0.
bovis (S5 Material). These isolates (upper branch) were considered as outliers among the M. bovis network, not fitting in the evolutionary scenario (i. e. mutation rate per year) of the rest of the species. A first explanation could be a problem in the sequences of bioproject PRJNA604127, but it would be surprising if this were to affect all isolates of this project in a uniform way. Furthermore, the only one M. bovis strain from Nigeria outside this bioproject (ERR1679654 from PRJEB15857) is in the same clade, and with the same long branch. This tree shape at least indicates that M. bovis is under evolutionary pressure in Nigeria. Another explanation would be the particular context of Nigeria, which, as we have shown here, already presents an extended specificity of evolution of L4. 6. 2.
Nigeria is also highly diverse, with growing economic resources, and a with a rich history and very diverse human genetic diversity and specific agriculture development history  [46] [47] [48]. We believe that there is an urgent need to increase sequencing in this country, and more generally in sub-saharian Africa. We recall, for example, that there are much too few genomes originating from african countries in the NCBI genome databases relatively to their demographic weight. Given the public health and also the anthropological interest to find the origin of the disease it would also be interesting to target circulating MTBC lineages, as we have done here, such as L5-L6, in new ambitious Africa-centered genomic research programs, because of the low number of genomes currently available, and because the latter is evolving and presents cases of multiple antibiotic resistance.
Acknowledgments We are deeply grateful to  Prs Lovett Lawson † , and  Luis Cuevas  † without whom this study would have never existed. We would also like to thank  Dr. Jose Dominguez ,  Dr. Barbara Molina-Moya , for giving us access to MTBC isolates and/or archival material from previous studies. We are grateful to  Pr Erick Denamur , Head of  IAME ,  UMR1137 INSERM-Universite  Ṕaris-Citefor his welcome and support. We are grateful to  Mustapha Gidado  (Executive Director of  KNCV Tuberculosis Foundation ) for connecting us with  M. Tukur Panda , with KNCV in Kano, Nigeria. All computations have been performed on the"Mesocentre de Franche-Comtesuper-computer facilities".
Acknowledgments: We would like to thank the  Swedish Radiation Safety Authority, SSM, and Region Normandy, Caen, France  for providing economical support for our research activities. We would also like to thank  Soukaina Kawni  for their discussion about DNA damage and  Traimate Sangsuwan  for their valuable comments and discussion. We highly appreciate the support of  Molecular Attraction AB, Lech Ignatowicz , and  Johan Paleovrachas , as well as  Matt Mullenweg.
These measures of interference need large datasets that can be of various kinds. One can use cytological markers of CO sites (e. g. Mlh1, COSA-1, recombination nodules) and determine their distribution along meiotic chromosomes. The metric used to describe CO distribution is, in this case, the length of axis/SC (in mm) between two adjacent events, which is likely the most relevant mechanistically  [23, 30, 38]. COs can also be detected genetically using DNA polymorphisms between the two parents, an approach that has become more powerful with increased sequencing capability  [39] [40] [41] [42] [43]. In this case, the distance between two adjacent COs is measured in the number of DNA base pairs. While this measurement can be very powerful, allowing highprecision mapping of CO sites and analysis of large populations, it has some limitations.
Acknowledgements We thank  Marcel Ernst  and  Wayne Crismani  for their helpful comments and  Neysan Donnelly  for proofreading the manuscript. We are grateful to  Stéphanie Durand ,  Simone Köhler ,  Benjamin Pigeard  and  Karine Budin  for the cytology images in Figure 1, and to  Andrew Lloyd  his help in designing Figure 3.
INTRODUCTION 2] [13] [14]  Therefore, the molecular profiling of tumors may be important to guide treatment decisions in patients with mCRPC and HRRassociated gene alterations, particularly for those involving BRCA. Practice guidelines generally recommend genetic testing of patients with mCRPC for mutations in DNA repair deficiency genes, particularly HRR-associated genes, to help tailor treatments to specific patient populations. 15 ] [22]  Niraparib, a highly selective PARP-1 and PARP-2 inhibitor approved for several indications, including ovarian, fallopian tube, and primary peritoneal cancers in select patients,  [23] [24] [25] [26] [27]  is being studied in patients with mCRPC in the ongoing phase III MAGNITUDE trial (ClinicalTrials. gov: NCT03748641). In MAGNITUDE, of 423 HRR-positive (HRRþ) patients enrolled, 225 (53.
DISCUSSION The results from IA2 of MAGNITUDE confirm that after a median follow-up of 24. 8 months in patients with BRCA1/2 alterations, the combination of niraparib plus AAP continued to improve rPFS, demonstrating a 45% reduction in the risk of radiographic progression or death, which corresponded to an extension of the median rPFS by 8. 6 months over placebo plus AAP, yielding a median rPFS of >1. 5 years. The clinical relevance of the benefit in rPFS was supported by delays in time to symptomatic progression and time to initiation of cytotoxic chemotherapy for the BRCA1/2 subgroup and the total HRRþ population treated with niraparib plus AAP versus placebo plus AAP. Furthermore, while OS data are still maturing and a final analysis of the MAGNITUDE trial is planned, there was a nonstatistically significant improvement in OS observed in the stratified analysis for the BRCA1/2 subgroup, with a more robust effect observed in the analysis that accounted for imbalances in baseline characteristics.
ACKNOWLEDGEMENTS We thank the patients who participated in this study, along with their families and caregivers, and the study teams who were involved at each participating institution. Medical writing support was provided by  Emanuela Marcantoni, PhD ,  Meredith Rogers, MS, CMPP , and  Jessica Deckman, PhD , CMPP, of  The Lockwood Group (Stamford, CT, USA ), which was provided in accordance with Good Publication Practice ( GPP 2022 ) guidelines and funded by  Janssen Research & Development, LLC. reimbursements from  AstraZeneca ,  Bayer , and  Janssen. AJPdSG received honoraria for lectures/speakers' bureau fees from  Adium Pharma ,  Astellas ,  AstraZeneca ,  Bayer , and  Janssen ; and travel, accommodations, and expense reimbursements from  Astellas  and  Janssen. EJS has stock or other ownership of Fortis and  Teon Therapeutics ; received honoraria from  Janssen  and  Johnson & Johnson ; and received consulting or advisory role fees from  Fortis  and  Janssen.
Results and Discussion To adequately detect target species, molecular assays need to be specific to the species of concern, highly sensitive to low or degraded DNA quantities, and free from environmental inhibitors  [43]. Specificity is key to successfully designing eDNA assays. Since Agrilus is the largest described animal genus  [27] , it is particularly important to demonstrate that specific primers can be designed to readily and accurately detect the target taxa. In the study by Kyei Poku et al. [36] , the similarity of the targeted gene region for EAB was compared to other congeners and other taxa from an online database to make the assay species-specific; however, specificity of a molecular assay, such as LAMP, needs to be validated with extracted DNA of other taxa. Kyei Poku et al. [36]  conducted specificity testing with extracted DNA of mostly North American co-occurring fauna including four Agrilus and two Scolytinaes, and none amplified with the EAB LAMP primers.
Acknowledgments: We would like to thank  Anthony Vastano  at  Rutgers University  for coordination and shipment of DNA extractions from USA to Europe,  Amanda Roe  at the  Great Lakes Forestry Centre, Canada  for advice on DNA amplification and primers and BBB samples,  Toby Petrice  from  USDA Forest Service  for BBB specimen, and  Davide Rassati  from  University of Padova  and the Euphresco project 2020-A-337-'Developing and assessing  surveillance methodologies for Agrilus beetles ' for other non-target specimen.
Quantification of tetraiodothyronine (T4) Homogenates of the fish tails were prepared according to the protocol for VTG and TH measurements described in detail in Part A  (Pannetier, Gölz, et al. , 2023). T4 concentrations in homogenate samples (supernatant) were measured using a commercial T4 ELISA (Thyroxine Competitive ELISA Kit, Catalog Number EIAT4C; Invitrogen Thermo Fisher Scientific). The homogenate supernatants were further processed according to the manufacturer's sample preparation guidelines for human serum and plasma samples and analyzed following the manufacturer's product information sheet. The plates were read at 450 nm on a Thermomax plate reader (Molecular Devices), and data were analyzed, as means of sample duplicates, on the associated Softmax software. The limit of analytical detection for the T4-ELISA was 0.
Thyroid follicle histopathology Photomicrographs of sections of thyroid follicles were taken at a ×40 magnification under a light microscope (Aristoplan; Leitz) equipped with a digital camera (DFK 33UX264; The Imaging Source) and analyzed with NIS-Elements D software (v. 5. 02. 00; Nikon Europe). Measurements of the diameter of the thyroid follicles and the thickness of the thyroid follicle epithelium were performed with Fiji ImageJ software (Rasband;  Schindelin et al. , 2012). Five follicles per fish and five measurement points evenly distributed over the epithelium per follicle were selected according to the following criteria: Range in follicle size was ensured (large, medium, small), and only thyroid follicular epithelia obviously uniformly cut at right angles were selected (oblique parts characterized by, e.
Eye histopathology Sections were acquired as described above. For each fish, a single bright-field image of a section containing a whole eye or an eye segment with a visible optic nerve was captured using a ×10 (adult fish) or ×40 magnification lens (juvenile fish). Eye diameter and thickness of the RPE were measured using the open-source Fiji ImageJ software (Rasband;  Schindelin et al. , 2012). The diameter of the eye was measured once at its widest point, whereas the thickness of the RPE was determined as the mean of eight measurements evenly distributed across the RPE with four measurements taken on each side of the optic nerve (Figure  3 ). Areas that exhibited detachment or cracks in the examined layers or any kind of artifacts were exempted from the analysis. Eye size correlates with fish size, which is why the relative eye size was calculated.
Method Animals Seventeen C57BL/6J-Tg (Thy1-GCaMP6f) transgenic mice (Jackson Lab) aged at least 11 weeks at the beginning of the experiments were used in this project (male, n = 10; female, n = 7). The animals were group-caged until implantation was performed (see below). They were kept in cages (46 × 29 × 25 cm) enriched with tube and shelter under otherwise standard laboratory conditions (12/12 h lightdark cycle with lights on at 8:30 p. m. and room temperature at 22. 2 °C). There was unlimited access to food and water until they were under food restriction protocols (see below). To reduce the use of animals, data were collected twice from the same mice as a general rule. Between the two tests, at least 2 days of training were carried out. All the procedure was approved by Directive 2010/63/EU guidelines on animal ethics (referral number: 2020112716449512-28454 approved by the ethical committee CEEAVDL).
In those cases, the top of the lens was first covered with a Kwik-Cast (WPI) after lens implantation. The baseplate implantation was done at least 2 weeks after the first surgery. To set the optimal distance between the lens and the baseplate, the plastic base plate was attached to the miniscope (Inscopix), and then aligned parallel to the GRIN lens. The distance was adjusted manually to maximize the focus of GCaMP6f expressing cells for each animal. When the optimal field of view (FOV) was observed on the acquisition software (DAQ box, Inscopix), the miniscope was raised slightly higher to avoid over-shrinking of the dental cement. Metabond was applied to secure the baseplate and lens, and the plastic cap of the baseplate was then screwed on.
For session 1 and session 2, the arena was itself similar but different environmental cues such as visual cues, odors, noises, and recording rooms were used (room A for session 1, room B for session 2). To encourage the mice to explore, food rewards were given occasionally. Twenty minutes after the end of first session, the animals received anisomycin (150mg/kg, sc, n = 11, or ip, n = 6) or a vehicle (PBS 1x) in a control experiment. All behavioral recordings were made by Media Recorder (Noldus) synced with nVoke recording software which was simultaneously recording the activity of CA1 cells activities. After each session, the arena was cleaned with 75% Ethanol and water. On the second day, the animal explored the same arenas using the same procedure, except that saline was administered instead of anisomycin.
Data acquisition Calcium imaging was performed using a one-photon miniaturized fluorescent microscope (nVoke; Inscopix, CA, USA) that can be mounted on the head of a mouse while the animal freely behaves. The data acquisition software (IDAS; Inscopix) was used at a frame rate of 20 Hz with LED intensities at 40 -50 percent (0. 8 -1 mW) and gain at 1 -1. 5 that was optimized for each animal. Ca 2+ imaging and behavioral recording were synchronized and triggered via TTLs to Media Recorder (Noldus) to align calcium transients and behavior. After 20 minutes from the start of the experiment, the data acquisition was automatically terminated.
Data analysis Processing Inscopix data processing software (IDPS; Inscopix) was used to process all the acquired Ca 2+ imaging data (1440 × 1080, 20 fps). As the FOV was manually aligned for each day of recording by aligning with the blood vessel(s), all the video from the same test for each animal was registered as time-series which considered videos added to time-series as a list of the functions. Then the original Ca 2+ imaging video was spatially downsampled by 4 and cropped at an optimal FOV for each animal. After preprocessing, a spatial filter and rigid motion correction were applied. Constrained non-negative matrix factorization for endoscopic data (CNMF-E) was used to identify regions of interest (ROIs). CNMF-E is one of the cell detection methods which is optimal for analyzing one photon microscopy data  52.
Place field analysis Behavioral data which was extracted from Ethovision XT (version 15 or 16, Noldus) and Ca 2+ events were aligned and analyzed by custom Python code. The time when mice were not exploring was excluded (speed > 1cm/s). The square arena was divided into 256 bins (16x16, size 2. 5cm x 2. 5cm). For each bin, the occupancy time of the mice spent as well as the number of Ca 2+ events were calculated. The rate map of a cell was calculated from Ca 2+ events in a bin divided by total occupancy time in the bin. Then a Gaussian smoothing filter (σ=2 bins) was applied. The spatial correlation was calculated by Pearson correlation compared to the rate maps in two sessions in Room A or Room B. We then assessed the level of similarity in spatial representations from different sessions by Pearson correlation (Pearson's r) using the smoothed rate activity maps.
For histology, 40 µm coronal sections were made by cooled microtome (-20 °C, Leica CM 3050 S, Paris, France). All the brain slices were mounted onto the slides directly after cutting. Vectashield® mounting medium with DAPI (Vector Laboratories, Burlingame, CA, USA) was applied to the slides and then covered by a cover slip. Slides were stored at 4 °C. All the micrographs were taken by a Zeiss Z. 2 Imager microscope in emitted-light mode using Zeiss ZEN software to check the expression of Ca 2+ indicators as well as the location of lens implantation.
Statistics All the statistical analysis was performed using Statistica and XLStat. Explanatory variables that have been used in our analysis included for most of the tests: "session" (A2 vs B2) or "room" (A vs B), "coactivation on day 1" (uniactive vs coactive), condition (ANI, VEH, ANI-24h). When required following a significant effect including multiple experimental groups, we ran multiple planned comparison tests using Holm-Bonferroni corrections. All the details of the statistics, the tests used, and their results are mentioned in the legend and the manuscript and are fully provided in supplementary information.