dataesr/scientific-paragraphs-categorization huggingface dataset:
Regional involvement in BIR Studies investigating the regional impact of the INSR on memory and cognition in rodents have only recently begun to be explored. Targeted knock-down of the INSR in the hippocampus impaired memory  [194]  while knockdown in the hypothalamus may have an indirect effect on memory through changes in whole-body metabolism  [193]. These data suggest that while the INSR itself may contribute to cognition within the hippocampus, the INSR in other regions, including the hypothalamus, may indirectly be involved in mediating cognition through changes in whole-body metabolism. However, whether some regions are more vulnerable to BIR and why has not been investigated. To do this, a vast descriptive study investigating the development of BIR across brain regions as AD progresses would need to be undertaken.
Remaining Questions/Concepts Many questions about insulin resistance in the brain remain. Given the current state of knowledge, we reiterate our definition of BIR: a complex condition that encompasses one or more causes for an inadequate response of the brain and cerebral vasculature INSR to insulin, including as it may relate to CNS insulin availability, CNS INSR and isoform expression, and/or downstream signaling events of the INSR in the brain. So far, data suggest that BIR correlates with cognitive impairment  [10]. Why and how BIR arises remains to be elucidated and investigated. And, importantly, the functional and clinical consequences of BIR, including in aging and AD, continue to be explored. Despite the clear link between BIR and AD, there are potential confounding factors that likely influence this relationship.
Acknowledgements This work was funded by a Supplement from the  United States National Institute of Health (NIH) -funded  Diabetes Research Center  at the  University of Washington   P30 DK017047-44  (to E. M. R. ), as well as  NIH  grants  RF1 AG059621  and  RF1 AG074549  (to Z. A. ), and a  Canadian CIHR  grant  PJT 168927  (to F. C. ). F. C. was a  Fonds de Recherche du Quebec-Sante  (FRQ-S) research scholar and M. L. was supported by a scholarship from the  FRQ -S. The work was also funded by the  LIA OptiNutriBrain  (X. F. , F. C. ) and the  RRI Food4BrainHealth  (X. F. and F. C. ). The APC was covered by X grant (Z. A. ). Parts of the figures were drawn by using pictures from  Servier Medical Art  as noted in the figure legends. Servier Medical  Art by  Servier  is licensed under a Creative Commons Attribution 3.
Objectives The objective of this systematic review was to provide an overview of current developments and potentially available therapeutic options for spondyloarthritis (SpA) in the coming years. Methods We conducted a systematic review of 17 national and international clinical trial databases for all disease-modifying antirheumatic drugs (DMARDs) for SpA that are already marketed, in clinical development or withdrawn. The search was performed on February 2023 with the keywords "spondyloarthritis", "ankylosing spondylitis" and "psoriatic arthritis". For each molecule, we only considered the study at the most advanced stage of clinical development. Results Concerning axial SpA (axSpA), a total of 44 DMARDs were identified: 6 conventional synthetic DMARDs (csDMARDs), 27 biological DMARDs (bDMARDs) and 11 targeted synthetic DMARDs (tsDMARDs).
METHODS We performed a systematic review of all DMARDs for SpA, including axial SpA (axSpA) and psoriatic arthritis (PsA), that are already marketed, in clinical development or withdrawn from 17 national and international clinical trial databases identified in the WHO registry network, according to the methodology that we previously published. 8  The search was performed in February 2023 in each database with the keywords "spondyloarthritis", "ankylosing spondylitis" and "psoriatic arthritis". First, we excluded trials unrelated to SpA or the evaluation of its activity, non-drug trials and duplicates. A second screening was then performed, and we also excluded dietary supplements and diets, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, non-immunological treatments and cell therapies.
Finally, we analysed only the immunosuppressive and immunomodulating agents and considered for each remaining molecule the study at the most advanced stage of clinical development (according to the current definitions for phases I, II, III and IV). Two authors (AD and CS) independently sorted the trials, with arbitration by consensus with two other authors (RF and GB). Then, the molecules were classified according to conventional synthetic DMARDs (csDMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs) in the same way, following the 2013 Smolen's DMARDs nomenclature. 9  Molecules were classified into the three categories 'marketed', 'in development' and 'withdrawn' based on the information collected in the databases and by crossreferencing internet searches. The molecules still in development in theUSA or Europe but already marketed in Asia or Russia were classified as in development.
RESULTS Our search was performed across 17 national and international clinical trial databases identified by the WHO (table  1 ). For each keyword, the total number of clinical trials, their sorting and then the classification of the molecules and their stage of development are summarised in figure  1. Overall, the search identified a total of 3574 trials, among which were identified 63 distinct DMARDs. Among the DMARDs, 9 are csDMARDs, 37 bDMARDs and 17 tsDMARDs (figure  1 ). The development phase, status and mechanism of action of the targeted treatments currently in development are summarised in tables 2-4. The development phase and mechanism of action of the withdrawn DMARDs are in table  5. Table  1  List of international and national databases of clinical trials used for this systematic review.
In addition, we remain dependent on keywords from the description of clinical trials, especially for phase I trials because they evaluate healthy individuals, but also on updates from manufacturers, which can change the status and development stage of clinical trials. However, the marketing process of a molecule is long and one can be aware of the molecules already in phases I and II to have an idea of the potential molecules we will be dealing with in the coming years. The major strength of this study is its overview of all clinical trials included in 17 international databases and the analysis and summary of all data available for each molecule.
Conclusion This systematic review identified 63 DMARDs evaluated for axSpA and PsA: 9 csDMARDs, 37 bDMARDs and 17 tsDMARDs. Although 17 DMARDs are already marketed, 26 distinct targeted therapies are currently in clinical development, including 18 for axSpA and 15 for PsA. Contributors The authors confirm contribution to the paper as follows: study conception and design: AD, LA and RF. Data collection: AD, CS and RF. Interpretation of results: AD, CS, GB and RF. Preparation of manuscript: AD, LA and RF. All authors reviewed the results and approved the final version of the manuscript. Guarantor: RF. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests AD declares that she has no competing interest.
1167). In other words, it allows us to 'investigate how [discursive] practices, events and texts arise out of and are ideologically shaped by relations of power and struggles over power'  (Mogashoa, 2014, p. 105). The analysis was conducted using IRaMuTeQ  (Ratinaud, 2009) , an open-source software for computational textual analysis, which algorithmically dissects textual corpora into thematic clusters based on the linguistic principles of lexicometry, allowing us to explore and compare the discourse employed in different textual corpora  (Chaves, dos Santos, dos Santosa, & Larocca, 2017; Ratinaud, 2009). While the use of IRaMuTeQ remains somewhat experimental, some scholars have been integrating it into their research enquiries as a supplementary tool for critical discursive analysis  (Ramos, do Rosário Lima & Amaral-Rosa, 2019).
To summarise, the steps for my analysis were as follows: 1. Downloaded all three datasets from the Commission's website  2. Identified the open-ended questions and replies and started building a separate file with these data (first as CSV and then as TXT, which is the compatible file type for IRaMuTeQ) 8 Global Media and China 0(0) 3. Translated the data using the Commission's official translation tool, and then formatted the data according to IRaMuTeQ's requirements, using the respondents' countries and each consultation dataset as an identifying variable 4. Conducted a DHC analysis on the dataset 5. Created lists of words comprising each cluster (or words of interest more broadly) and compared their usage across datasets and countries (Specific Words Analysis).
Findings and discussion Due to space and word limitations, the main findings, which were inferred from the DHC classes found in Figure  1 , are presented in bullet points. The findings are drawn from examining the words structuring each cluster, allowing us to understand the predominant points of discussion of our textual corpus, as well as their prevalence compared to the other discursive points. For instance, Class 5 (Green colour), which contains TSs referring to the pandemic, has a size of 5. 5%, indicating that, while it contained TSs that were unique enough to be listed in a separate cluster, it covered a very small part of the whole corpus. This is reasonable considering that the pandemic was only discussed in the consultation regarding the DSA. The findings were bundled based on my interpretation of the texts found in each cluster, as well as on a closer reading of my dataset.
Acknowledgments The author would like to thank  Pierre Ratinaud  for his guidance on how to make the most out of IRaMuTeQ,  Nikos Smyrnaios  for his feedback, and  Simran Agarwal  for her precious comments. The author would also like to thank participants of the workshop on "Radical Approaches to  Platform Governance ," where a previous version of this article was presented, for the inspiring conversations around this topic.
, 1992; Norberg et al. , 1991). However, despite a rapidly expanding body of research on Atlantic halibut ecology  (Shackell et al. , 2022) , the variability in spawning timing and sex-specific behaviors of the species in the wild remains largely unstudied, in part because of the difficulty observing halibut in the winter spawning season, especially in the Gulf of St. Lawrence that is seasonally covered by sea ice. In the present study, we used high-resolution depth, temperature, and acceleration data from recovered PSATs to characterize the spawning behavior of Atlantic halibut in the Gulf of St. Lawrence. Building on previous studies observing presumed spawning rises in Atlantic halibut and other flatfish, we identified presumed spawning rises in female and male halibut and determined their dates of occurrence, amplitude, and frequency.
, 2020; James et al. , 2020; Le Bris et al. , 2018; Murphy et al. , 2017). Two models of tags were used: X-Tag PSATs from Microwave Telemetry, Inc. , which recorded depth (±0. 34 to 5. 38 m resolution from 0 to 1296 m), temperature (±0. 16 to 0. 23 C resolution), and light intensity level (±4 Â 10 À5 lx resolution at 555 nm) every 2 min (Table  S1 ), and MiniPATs from Wildlife Computers Inc. , which recorded depth (±0. 5 m), temperature (±0. 1 C), and light intensity (5 Â 10 À12 to 5 Â 10 À2 W/cm 2 ) at 5-15 s resolution throughout the deployment period (Table  S1 ). MiniPATs used in the 2017 deployment also recorded acceleration (n = 36). Tags were preprogrammed to release from their host fish at a specific date $1 year following tag deployment. High-resolution archived data sets were available from tags that were physically recovered.
| Spawning rise characterization To provide a complete characterization of each presumed spawning rise, the depths and times were recorded at the start, end, and peak of every rise for both female and male halibut. Time between successive rises was calculated by subtracting the time at the peak of one spawning rise from the time at the peak of the next spawning rise. Furthermore, the effects of several environmental and individual factors on two characteristics of special interest, the date of the first presumed spawning rise and the total number of spawning rises, were evaluated using generalized linear models (GLM). GLMs were run only on the female halibut spawning rise data because of the higher confidence in the female spawning rise detection, and the understanding that females constrain reproductive potential more than males due to greater physiological requirements for producing eggs  (Bateman, 1948; Coleman & Jones, 2011; McBride et al.
| Acceleration MiniPATs deployed in 2017 (n = 36) were equipped with three-axis accelerometer sensors. Accelerometer data at a frequency of 0. 2 Hz were archived in the tag and were accessible from physically recovered tags (n = 25). A previous study has shown that acceleration data from externally attached PSATs can be used to infer fish activity  (Nielsen et al. , 2018). In the present study, we aimed to determine whether presumed spawning rises were associated with noticeable acceleration patterns. To do so, the total acceleration relative to F I G U R E 2 Proportion of halibut across all tagging years, grouped by sex, considered to be within their spawning period on a given day. Only halibut exhibiting presumed spawning behavior were included in this analysis. Presumed spawning periods were defined as the period between and including the first spawning rise and last spawning rise for each individual.
| DISCUSSION In the present study, we used the high-resolution time series recorded by PSATs, geolocation of individual tagged fish, and information on halibut sex to characterize the presumed spawning behavior of Atlantic halibut in the Gulf of St. Lawrence. An inherent limitation of electronic tagging data to study fish behavior is the necessity to infer behaviors from patterns observed in the time series data. Analyses of depth time series recorded by PSATs deployed on Atlantic halibut revealed unique rises (up to 284. 00 m) off the seafloor by females and males with peak occurrence in February. We interpreted these unique ascents as spawning rises following previous interpretations of similar rises observed in depth time series recorded by electronic tags deployed on several groundfish species, including Pacific halibut  (Seitz et al.
ACKNOWLEDGMENTS We thank all the  Gulf of St. Lawrence  fish harvesters involved in project planning, tag deployment, and tag recovery. Major funding for this research was provided by the  Natural Sciences and Engineering Research Council of Canada  via the  Strategic Partnership Grants for Projects Program 's contributions to " Quantifying spatial dynamics and stock structure of Atlantic halibut within the Gulf of St. Lawrence to improve sustainable exploitation and management ," and  Dominique Robert  was supported by the  Canada Research Chairs programme.
03 mol L -1 in Milli-Q water yielded a pH of ~3. 13. The relationship between CO 2 partial pressure and CO 2 concentration in water Milli-Q, as well as the pH of the injection solution, was calculated using PhreeqC (v. 3. 6. 2) code (Parkhurst and Appelo, 2013) and the PhreeqC database. 9. 90 mL of the filtered output solutions were immediately acidified by adding 0. 1 mL of 65% HNO 3 to prevent possible precipitation of calcite. Thereafter, the Ca concentration was measured using Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES) employing a Perkin Elmer Optima 8300 with a Ca detection limit of 6. 3 × 10 -6 M and 3% of analytical uncertainty. The second series of experiments was conducted under atmospheric pressure (Fig. 2b , Fig. S2 ). In this flow-through system, an HCl solution tank of 5 L was connected to a peristaltic pump that injected the solution into the core at a constant flow rate of 0.
Effects of dissolution patterns on permeability changes The permeability changes in the Pont du Gard Limestone are related to the dissolution patterns. Permeability shows a marked increase when wormhole forms in the CO 2 -rich water experiments. Although the number of permeability measurements is limited (5 values for CO 2 injection experiments) to draw a solid mathematical relationship between porosity and permeability, assessment of the obtained data from these experiments (Table  2 ) implies the following empirical expression that relates the two parameters k∝ϕ 24  (9) This correlation is consistent with other powerlaw relationships for wormhole-controlled permeability enhancement in other limestones  (Hao et al. , 2013; Menke et al. , 2015; Menke et al. , 2017; Noiriel et al. , 2005; Smith et al.
, 2011; Miller et al. , 2019). The values of the elastic moduli of the inclusions are K i = 10 -4 GPa, and G i = 0 GPa, and the initial elastic moduli of the host medium correspond to those of calcite (K * (t 0 ) = 71 GPa, and G * (t 0 ) = 31 GPa). The functional form of P and R can be found in rock physics handbooks  (Mavko et al. , 2009). The homogenization problem described in Eqs. (  10 ) and (  11 ) were iteratively solved using MATLAB. Fig. 10  shows that the evolution of elastic moduli with the variation in dissolution-induced porosity depends primarily on α. Calculated elastic moduli agree well with the experimental data when α varies between 0. 1 and 0. 125, which is in close agreement with those calculated for other limestones, i. e. , 0. 08 < α < 0. 2  (Arson and Vanorio, 2015; Fournier et al.
Acknowledgments This work has received funding from the  European Union 's  Horizon 2020 Research and Innovation Programme 2014-2018  under agreement No. 847593 , specifically from the WP MAGIC. A. V. acknowledges funding from the  University of Barcelona  under Travel grants for Ph. D. students in Earth Sciences 2020. V. V. acknowledges funding from the  European Research Council (ERC)  under the European Union's  Horizon 2020 Research and Innovation Program  through the  Starting Grant GEoREST  (www. georest. eu) (Grant agreement No. 801809 ). J. C. and J. M. S. also acknowledge funding from the  Catalan Government  through project  2017SGR1733. IDAEA -CSIC  is a  Centre of Excellence Severo Ochoa  ( Spanish Ministry of Science and Innovation , Project  CEX2018-000794-S  funded by  MCIN/AEI/10.
Material The fossil specimens studied in this work were unearthed during the 2008e2020 field surveys of the BB Section. These former specimens correspond to fossils of hippo skeletal elements that are temporarily housed in the Palaeoanthropology Laboratory of the Museo Nacional de Ciencias Naturales (MNCN, CSIC) for study. Referred specimensdPartial skull preserving two fragments of the maxilla with P2 to M3 (BB'09C2IIS. 1515 þ BB'09C2IIS. 1526, BB'09C2IIS. 1522 þ BB'10C2II3S. 1502 þ BB'08C2IIP. 1419; Fig. 2 ) and posterior part of the neurocranium (BB'09C2IIR. 1403 þ BB'09C2IIS. 1407; Fig. 3 ); a fragment of right maxilla with M2 and M3 (BB'11EFIIK. 1407; Fig. 4   B3a, b ); distal half of a left femur (BB'12E-FIIO. 1102; Fig. B3f-h ); fragmented calcaneus (BB'08EFIIH. 1301; Fig. B3i-k ). In addition to the unpublished specimens, comparative data and the study of other materials have been used.
Concealment of anatomical contour structures by cusps was avoided due to a non-standardised view at the time of photography. The measurement of the different landmarks and semilandmarks on all specimens has been carried out in Viewbox 4 software (dHAL software, Kifissia, Greece;  Bastir et al. , 2019). The sliding of the semilandmarks has been carried out with the specific tools provided by the same software. The original coordinates have been extracted and organised for the subsequent statistical analysis. To ensure that the intra-observer measurement error has not significantly affected the results, a permutation test has been carried out following the proposal of  Klingenberg (2011). The intra-observer error was accepted after testing that the largest Procrustes distance within 5 measurements of the same individual was smaller than the smallest Procrustes distance between 10 specimens of different individuals.
Data processing and analysis and the production of graphical results were implemented in the software Morphologika2 v2. 5  (O'Higgins and Jones, 2006) , MorphoJ 1. 07a  (Klingenberg, 2011) , Past 4. 03 and RStudio. To assess differences in tooth element morphology between taxa and sites, independent PCA dimensionality reduction analyses were performed for M1 and M2, detailing the variability picked up by the first three PCs in brackets in the title of the axes. The analyses include the graphical expression of the shape change associated with their axes. To test statistically the differences between taxa assessed based on procrustes distances, the distance-based test procrustes ANOVA was used. Due to the paucity of data, only the taxa H. antiquus and H. amphivius (living) could be statistically evaluated, so a post hoc test was not necessary.
gorgops shows very few variables with significant differences (see Table  C7 ). The results of the multivariate analysis including the measurements of the premolar series (P2eP4) account for 52% of the variance in PC1, 18. 59% in PC2 and 10. 9% in PC3 (Fig. 10a, a' ). BB specimens are included in the variability recorded for H. antiquus, with values close to those of Cal Guardiola in the first two components. PC3 highlights the variability between both laterals of the same individual. H. antiquus presents mean values notably different from those of living H. amphibius, more positive in PC1 and negative in PC2. In contrast, the three specimens for which data are available for H. gorgops are closer to the average of H. amphibius, especially the Olduvai Gorge specimen and the Turkana specimen for PC2.
antiquus. In general, the BB materials present morphologies and measurements intermediate between the more "advanced" forms (according to the term used by  Kahlke (2001)  for morphologies similar to S. Oreste specimens) and those more typical of H. antiquus (such as the Collecurti specimens). Their small dimensions (especially in the appendicular elements) and the general morphology of M1 and M2 resemble some of the Cal Guardiola specimens, although multivariate analyses of molar measurements bring them closer to the data from Barranco Le on-5 or Untermassfeld. In any case, the BB hippo specimens studied in this work coincide within the morphological and biometric margins of H. antiquus from the Epivillafranchian. It is interesting to mention the position in morphospace of the specimens without specific determination from Aboucherit  (MNHN 195e13$94; van der Made, Pers.
Conclusions According to the data and analysis presented here, we can conclude that the studied Hippopotamus specimens, from the Barranc de la Boella Section, fit within the characteristics considered for the species Hippopotamus antiquus. The biometric values and anatomical characteristics of these specimens are consistent with the morphological variability found in the hippopotamuses previously recorded in the Epivillafranchian of Europe. Even so, the great overlap in the phenotypic characteristics of H. antiquus specimens dated with different chronologies reinforces the idea of considering a single species of hippo in the Early Pleistocene and part of the Middle Pleistocene in Europe, when the extant H. amphibius is first reported from this continent. Likewise, data from the fossil record (chronological and geographic distribution), together with anatomical assessment, point to a single entry of hippos into Europe during the Early Pleistocene.