dataesr/scientific-paragraphs-categorization huggingface dataset:
Phylogenetic reconstruction and positive selection analyses For each of the 1649 alignments, a Maximum-Likelihood phylogeny was reconstructed using RAxML v. 8. 2. 11 with the following parameters: -x 12345 -# 100 -f a -m GTRGAMMA -p 12345 (Figure  1B ). Deep (>200m) species (tips) and monophyletic groups of deep species (nodes) were labeled as "Foreground" branches for positive selection analyses (Amphiuridae: 46 species; 11 independent events of deep-sea colonization; Ophiodermatidae: 7 species; 4 independent events; Ophiomyxidae: 10 species; 4 independent events; Ophiotrichidae: 4 species; 4 independent events). Then, the package HyPhy was used to conduct several positive selection analyses (Figure  1C ): 1) BUSTED (Branch-site Unrestricted Statistical Test for Episodic Diversification)  (Murrell et al.
Gene Ontology annotations and amino-acid convergence analyses To explore which functions may be involved in deep-sea adaptation, the representative sequence of each of the 416 genes was extracted from the sea urchin Strongylocentrotus purpuratus genome and blasted against the nr database from NCBI using BLAST+. We used S. purpuratus as reference because sequence annotation for this species is of high quality (no highquality brittle star reference genome is currently available) and to use a single complete representative sequence for each gene. The top 50 hits were extracted and loaded in BLAST2GO v. 4. 1. for annotation  (Conesa et al. 2005). Mapping, annotation and slim ontology (i. e. GO subsets of broader categories) were performed with BLAST2GO using default parameters, except for the annotation cut-off parameter, which was set to 45.
sbg. bio. ic. ac. uk/~phyre2/)  (Kelley et al. 2015). The global stability of each model structure was then calculated using the 'stability' function of the program FoldX with default values  (Schymkowitz et al. 2005). For each site, the DDG value between 'deep-water' (mutant) and 'shallow-water' (wild-type) mutations was calculated, where DDG > 0. 5 kcal/mol indicates stabilizing mutations, DDG < -0. 5 kcal/mol indicates destabilizing mutation, and -0. 5 kcal/mol < DDG < 0. 5 kcal/mol indicates neutral mutations  (Khatun et al. 2004; Khan & Vihinen 2010).
Five genes involved in protein biogenesis are recurrently positively selected in deep-sea brittle stars We used 416 single-copy orthologs from 216 species (288 individuals) of four brittle star families (Figure  1A ) to examine patterns of positive selection in deep-sea species (>200m). For each gene of each family, we used four different positive selection methods and one method detecting relaxation of selection (Figure  1B-C ). Given that our dataset is not representative of the whole genome, we chose a stringent approach to focus on a few candidate genes displaying strong signals of positive selection. Therefore, we only kept candidate genes that had significant signature of positive selection in at least three methods and which also did not show relaxation of selection. We found 36 candidate genes in Amphiuridae, 9 in Ophiodermatidae, 6 in Ophiomyxidae and none in Ophiotrichidae (Table  S2 ; Figure  S1 ).
This suggests that these two genes are evolving faster not only in response to deep-sea conditions but also possibly in response to additional environmental conditions. CCTα, the sole candidate gene detected as significantly positively selected in three families in the shallow-deep contrast, did not display signatures of positive selection in shallow-water environments (Table  S3 ). It is a subunit of the octameric Chaperonin Containing TCP1 (CCT) complex, a cytosolic eukaryotic chaperonin having a central role in protein folding (Figure  2A -D)  (Bueno-Carrasco & Cuéllar 2019; Valpuesta et al. 2005). The three other CCT subunits present in our dataset, CCTd, CCTe and CCTh, did not display consistent signatures of positive selection; rather, while positive selection was detected at the site level in all subunits, relaxation of selection was detected in all 3 subunits in Amphiuridae (Table  S6 ), indicating that the accumulation of mutations in these subunits is not clearly due to natural selection.
Therefore, CCTa was the only one out of four subunits to show consistent signatures of positive selection across methods. The remaining four subunits of the CCT complex could not be tested as they were not present in our dataset. Interestingly, PFD3, a subunit of the hexameric co-chaperone prefoldin interacting with CCT  (Gestaut et al. 2019; Martín-Benito et al. 2002)  was positively selected in two families (Amphiuridae: MNM, MEME, BUSTED; Ophiodermatidae: MNM, aBSREL, MEME, BUSTED) (Table  1 ; Tables  S2, S6 ; Figure  2D ), although it was also positively selected in shallow-water Amphiuridae (Table  S3 ). The two other prefoldin subunits present in our dataset (PFD1 and PFD5) did not show a consistent signature of positive selection (Table  S4 ), suggesting that subunits of this co-chaperone can evolve relatively independently from each other.
This might be due to the different degrees of subunit specialization in CCT, as CCTα has intermediate binding properties (i. e. neither high ATP affinity nor high substrate affinity) compared to the other subunits (Bueno-Carrasco & Cuéllar 2019). Therefore, it is possible that CCTα can evolve more rapidly because it may experience less negative selection than the other subunits. In the same way, we tested three subunits of the hexameric prefoldin complex, and PFD3 was the only subunit to be consistently positively selected. While we acknowledge that we analyzed an existing dataset and thus did not test all subunits of both macromolecular complexes (4/8 in CCT; 3/6 in prefoldin), it appears surprising that individual subunits of macromolecular complexes can evolve relatively independently from each other.
Similarly, in a study on metabolic enzymes from 37 ctenophores, numerous sites associated with adaptation to depth, temperature or both were located close to the substrate binding region  (Winnikoff et al. 2019). A major substrate of the CCT complex and its co-chaperone prefoldin is actin, an essential cytoskeleton protein  (Martín-Benito et al. 2002). While it should be noted that CCTa is not directly involved in actin folding (actin binds the subunits CCTd, CCTb and CCTe)  (Llorca et al. 1999 (Llorca et al. , 2000)) , examination of cytoskeletal proteins is of interest due to their essential role in cells. Unfortunately, as actin and tubulin were not included in our dataset, no conclusions about cytoskeletal proteins of deep-sea brittle stars can yet be drawn. However, actin of deep-sea fishes has been extensively studied, showing that it displays structural adaptations to high-pressure enhancing stability  (Morita 2003; Koyama & Aizawa 2008; Wakai et al.
2015). Furthermore, convergent evolution in chaperones has previously been shown  (Draceni & Pechmann 2019) , and there is evidence that other groups of molecular chaperones such as HSP70 and HSP90  (Kim et al. 2013 ) are involved in deep-sea adaptation (Yancey 2020). For instance, the HSP70 gene family was expanded in a deep-sea mussel  (Sun et al. 2017 ) and convergent amino-acid changes have been reported in four out of five copies of the HSP90 protein in a hadal fish  (Wang et al. 2019 ). In our dataset, two HSP90 genes were present (HSP90b1 and HSP90ab1), yet neither showed signatures of accelerated evolution. Nevertheless, only the examination of whole genomes will give a complete view of HSP family evolution in brittle stars, which should be explored in further studies.
Limitations and outlook We acknowledge that our study lacks functional validation to demonstrate that the changes are truly adaptive (which would be experimentally demanding as CCT folds ~10% of newly synthesized proteins and we analyzed the sequences of more than 700 species), yet we minimized false inferences by applying stringent positive selection detection criteria. Furthermore, we used a proxy of functional validation by investigating in silico local and global protein stability in a dataset with great comparative power, both in terms of phylogenetic and environmental diversity. Finally, direct experimental testing on deep-sea organisms remains technically challenging, so we made use of the power of molecular data to indirectly reveal new insights in deep-sea adaptation. Further studies should include whole genomes to obtain a more complete view of deep-sea adaptation hotspots and possible mechanisms, such as recent studies on deep-sea fishes  (Gaither et al.
Acknowledgements We are grateful to  W. Salzburger  for providing access to the  HPC  sciCORE cluster and to  J. Sarrazin  and  S. Arnaud-Haond  for comments on a previous version of this manuscript. We thank  L. Bribiesca-Contreras  for help with R analyses. We thank three anonymous reviewers and the editorial team for valuable comments on a previous version of this manuscript. Calculations were performed at sciCORE (http://scicore. unibas. ch/)scientific computing center at the  University of Basel, Switzerland  and at DATARMOR (http://www. ifremer. fr/pcdm)scientific.
Data collection The following data are recorded: demographics, medical history, birth context for children <3 months old, vaccination schedule, temperature registered at home and at the PED, home fever management, time between when fever was first detected and when the infant was brought to hospital, date and time of admission and exit of ED, clinical examination at the admission, parental and medical concerns for the child, results of any tests performed, treatment received, diagnosis and orientation after the visit in the ED (return home or hospitalisation). The following additional data on day 15 were also collected by phone call to parents: clinical pathway, tests performed or treatments received in the meantime, child's condition now, utility of instructions for fever (online supplementary appendix 3) given at the end of the visit in the ED.
Electronic case report form Data for each patient participating in the research will be collected by an e-CRF developed by using Ennov Clinical. All information required by the protocol will be provided in the e-CRF, including data required to confirm compliance with the protocol and all data necessary for statistical analysis and to identify major deviations from the protocol. Entering, viewing or modifying data will only be possible via the e-CRF pages (input masks), at https:// nantes-lrsy. hugo-online. fr/ CSonline. The data will be stored directly from the e-CRF into the database hosted on a dedicated server, with controlled access. Any addition, modification or deletion of data will be recorded in a non-editable electronic file. The e-PRO module of Ennov Clinical will be used to managed the parent interview on day 15.
02. If the margin is included in the 95% CI, the result will be inconclusive. Both per-protocol and intention-totreat analyses will be performed. Differing results from the per-protocol and intention-to-treat analyses will be defined as inconsistent. 33 atistical analysis of secondary outcomes The incidence of fever without source in ED consultations will be estimated by pooling data for the two groups: experimental and control. The incidence of SBI and IBI in children consulting for fever without source will be analysed in the framework of a mixed logistic regression. Associated clinical symptoms, condition evolution, microbiological culture documentation and antibiotic resistance among isolated bacteria will be reported by using descriptive statistics. The diagnostic properties of the DIAFEVER prediction rule will be assessed considering only patients who will be recruited in centres applying the rule and during the ad hoc period.
Data monitoring Data monitoring will be performed by the research division promotion department. A clinical research associate will visit each site regularly to conduct quality control on the data reported in the case report forms. The members performing this function are not yet known. The on-site monitoring visits will be organised after making arrangements with the investigator. The clinical research associate should be able to consult the following on each site: the enrolled patients' data compilation records, the patients' medical and nursing files, study-related charts and the investigator file. No interim analysis is planned because the protocol of the study has been classified according to the estimated level of risk for the patient as low or negligible foreseeable risk (risk A).
EthICs AnD DIssEMInAtIon research ethics approval The data gathered during the study will be held in a computerised file, as per the 2004 amendment of the French data protection act of 6 January 1978. The protocol falls within the scope of the MR001 methodology applied by Nantes University Hospital. This study was submitted to an independent ethics committee on 17 May 2018 (no. 2018-A00252-53). The study was also submitted to the relevant Swiss Ethical Review Board and competent authorities for prior approval to include patients in Switzerland.
Acknowledgments We thank the two anonymous reviewers for their suggestions, which helped to substantially improve the manuscript. MSL is funded by  CNES. SB and JLD are supported by the  European Unions   Horizon 2020 research and innovation program  under grant agreements  694768  ( ERC  project  EUREC4A ) and  820829  ( CONSTRAIN  project). This work was supported by  CNES. It is based on observations with CALIOP embarked on CALIPSO. To process the CALIPSO, GOCCP, and ERA5 data, this study benefited from the  IPSL mesocenter ESPRI  facility which is supported by  CNRS ,  Sorbonne Université , Labex L-IPSL, CNES, and  Ecole Polytechnique.
Density functional theory calculations All the simulations discussed in the paper and in this Section have been performed at the ab initio level, using the Density Functional Theory (DFT) approach. DFT has therefore been used to both optimize the material geometry at zero temperature and to evaluate the ionic forces acting on each atoms along the AIMD trajectories. Most of the calculations have been carried out with the CP2K software  [50]  and some preliminary electronic structure relaxations have been performed with VASP  [51]. With C2PK, the DFT method is straightforwardly employed using the Quickstep module  [52, 53]  of the package. As in Ref. [54] , DZVP-MOLOPT-SR-GTH basis sets were used  [55]  along with planewaves ex-panded to a 800 Ry absolute energy cutoff and a 40 Ry relative cutoff.
ACKNOWLEDGEMENTS F. M. and M. L. B. acknowledge funding from the  H2020-424   FETOPEN  project NANOPHLOW number  766972. This work was granted access to the HPC resources of TGCC and CINES under grants  A5-A0070807364  and  A0070807069  by  GENCI. We thank  Vasu Kalangi  and  Lydéric Bocquet  for insightful discussions about GO membranes, and  Guillaume Fraux  for his help with Chemfiles/cfiles.
Weaknesses The in vitro production of red blood cells is possible and the produced cells proved safe in a preclinical trial [NCT0929266]. Recommendations have been made to move forward to an industrialized scale up 1   [20, 21]. However, mass production is not-yet achievable; this would require considerable investment and efforts. Regarding platelets, this status is far from being satisfactorily achieved. When available for clinical use, and contrary-in my opinion-to what is frequently claimed (in position papers), the transfusion-transmitted infectious risk is not completely overcome ; indeed, HSCs, iPS or even ESCs may contain endogenous (retro)viruses that can, in theory, be amplified with no regard to long-term outcome, especially as the endogenous retroviruses are regarded as potential innate immune makers and are capable of self-protecting against foreign infections  [20, 21]  but their effect on a foreign body has never been considered to the best of my knowledge and might, perhaps, be important, in spite of the fact that no related pathology has been reported following allogenous stem cell transplantation.
Subgroup analyses based on history of HF, pretrial EF, and other factors were also conducted including assessment of treatment by subgroup interactions. Forest plots were used to summarize the results of subgroup analyses. Analyses were performed with SAS software version 9. 3 (SAS Institute Inc). Results were considered statistically significant with a 2-sided P<0. 05 or 95% CI excluding 1. 0, with no adjustment for multiple comparisons.
DISCUSSION The overall results of VERTIS CV together with the recently published meta-analysis indicate that the effect of ertugliflozin on HHF in patients with T2DM with ASCVD is consistent with that found across the class of SGLT2 inhibitors. 9, 23 In the current prespecified analyses, we report more detailed data with ertugliflozin on HF-related outcomes. In comparison with other recent SGLT2 inhibitor CV outcome trials in patients with T2DM, the VERTIS CV population included the largest proportion of patients with a history of HF, 23. 7% of the overall trial population, similar to the proportion found in a typical diabetes clinical practice (20%-30%). 24 VERTIS CV also had the largest set of data on pretrial EF available, for 60. 7% of patients in the trial, facilitating additional analyses of CV outcomes based on the presence or absence of HF history, and EF values, as well.
Data Accessibility On request, and subject to certain criteria, conditions and exceptions (see https:// www. pfizer. com/science/clinical-trials/trial-data-and-results for more information) Pfizer will provide access to individual deidentified participant data from Pfizersponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The deidentified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal.
Methods We did a population-based survey in Rakai, Uganda, using data from the Rakai Community Cohort Study. The study surveyed all individuals aged 15-49 years in four high-prevalence Lake Victoria fishing communities and 36 neighbouring inland communities. Viral RNA was deep sequenced from participants infected with HIV who were antiretroviral therapy-naive during the observation period. Phylogenetic analysis was used to infer partial HIV transmission networks, including direction of transmission. Reconstructed networks were interpreted through data for current residence and migration history. HIV transmission flows within and between high-prevalence and low-prevalence areas were quantified adjusting for incomplete sampling of the population. Findings Between Aug 10, 2011, and Jan 30, 2015, data were collected for the Rakai Community Cohort Study.
Research in context Evidence before this study High-resolution spatial mapping of HIV disease prevalence revealed numerous geographical hotspots of high prevalence throughout the African continent. This information is used to target public health interventions to hyperendemic communities to maximise cost-effectiveness of interventions, and often with the implicit assumption that HIV hotspots serve as sources of transmission to the larger, low prevalence populations. We searched PubMed for all article types published between database inception and April 15, 2019, using search terms related to "HIV", "hotspots", "core groups", "spatial", and "Africa". Few studies have investigated the flow of HIV infection between foci of high prevalence (ie, hotspots) and relatively lower prevalence areas using empirical methods.
Added value of this study In this study, we used HIV deep sequence data from a population-based sample to reconstruct directed HIV transmission networks, and examine the epidemic dynamics between geographical hotspots with high HIV burden along Lake Victoria and surrounding inland communities. We used data from the Rakai Community Cohort Study, an open population-based cohort that provided a high sampling fraction of the communities, which is rare in phylogenetic studies, as well as detailed information on individual-level human migration patterns. We integrated HIV phylogenetic and human migration data, and showed that Lake Victoria and inland epidemics are largely distinct based on a sample of 293 phylogenetically highly supported transmission pairs. Where there is cross-community transmission, it is predominantly from inland to Lake Victoria fishing communities and not vice versa.
Implications of all the available evidence Our findings showed that within sub-Saharan Africa, HIV transmission networks in high prevalence areas can be largely disconnected from those in adjacent lower prevalence populations, and caution against equating and stigmatising HIV hotspots in sub-Saharan Africa universally as population groups that drive disease spread. Geographical targeting of high prevalence areas is essential for local populations in hotspots, but under the same conditions as in the fishing communities of the Rakai Community Cohort Study would have a limited effect on the HIV epidemic in neighbouring lower prevalence communities. Here, we integrated viral phylogenetic and epidemio logical data to empirically measure HIV transmission flows between high HIV prevalence hotspots on Lake Victoria and larger neighbouring inland populations with substantially lower HIV burden in the Rakai region of southern Uganda.
Study design and participants We did a population-based study using data from the Rakai Community Cohort Study (RCCS) in 36 inland communities of the Rakai region in south-central Uganda shown in figure  1A , and the main four fishing communities within 3 km of Lake Victoria. 13 The data were collected in two survey rounds in inland communities, and three survey rounds in fishing communities. For each survey round, the RCCS did a household census with GPS coding of household location, followed by a survey of consenting eligible participants aged 15-49 years to ascertain sociodemographic characteristics, sexual risk behaviours, health, and health service use. The RCCS included all age-eligible individuals capable of providing informed consent and resident within the RCCS communities for at least 1 month with the intention to stay.
Procedures To infer transmission networks by phylogenetic analysis, viral sequencing was done on plasma blood samples from all individuals who were infected with HIV who selfreported being ART-naive at the time of the survey. This selection criterion was motivated by the fact that selfreported ART use reflected actual ART use with high specificity and sensitivity, and that 90% of individuals who reported ART use had suppressed virus less than 1000 copies per mL of plasma,  18  below which viral deep sequencing was not possible within our protocol. 19, 20 Deep sequencing based on the protocol of Gall and colleagues  19  generated many sequence fragments that capture viral diversity within individuals (figure  1B ), which unlike Sanger sequencing, enables phylogenetic inference into the direction of transmission from sequence data alone.
21 hylogenetic transmission networks in the populationbased sample were reconstructed from deep-sequence data with phyloscanner,  20, 22  which addresses caveats in deep-sequence phylogenetic analysis such as read contam ination, and has an estimated false discovery rate in inferring the incorrect direction of transmission of 15-20%. 20 To capture uncertainty in phylogenetic inferences, phylogenetic relationships were evaluated in a large number of deep-sequence phylogenies sliding across the HIV genome. Pairs of individuals with evidence for phylogenetic linkage and transmission in one direction in at least 60% of phylogeny evaluations were identified and considered to be highly supported source-recipient pairs. The threshold was determined in analysis of pairs with epidemiological evidence on the direction of transmission.