dataesr/scientific-paragraphs-categorization huggingface dataset:
Study selection Participants with a diagnosis of dementia or cognitive impairment at baseline were excluded. Incident cognitive decline was assessed using the reliable change index (RCI) using the Chelunes method. 15 Since the cognitive data are drawn from different populations and with some variation in repeat testing times, this method allows standardization of reliable decline across cognitive tests with a fall in the RCI value greater than 1. 645, i. e. , changes exceeding the 90% confidence interval (CI) for RCI categorized as reliable. Follow-up cognitive testing was required to be after the minimum 1 year AHM exposure period and cognitive change was assessed subsequent to or concurrent with this. Cognitive tests were categorized as screening tests and tests of memory, executive function, attention, and speed of processing.
Data synthesis and analyses Meta-analyses were conducted for the endpoints of both cognitive decline and dementia. Because cognitive change is insidious, classification of event dates is problematic for cognitive outcomes. To reduce bias associated with different study designs and varied duration between cognitive assessments, logistic regression models were used with incident cognitive decline or dementia as the dependent variable. Since the effect of AHM class on cognitive function is thought to be pleiotropic, models examining class were adjusted at study level for baseline systolic BP or, where this was unavailable, for the presence of hypertension at baseline, plus age, sex, and education. Adjusted results were combined to produce a pooled odds ratio (OR). Raw data relating to the number of cases and controls for each class were also combined to produce an unadjusted pooled ratio.
Standard protocol approvals, registrations, and patient consents The review was registered with the international prospective register of systematic reviews (PROSPERO), registration number CRD42016045454. Ethical approval was obtained from the Science and Medical Human Research Medical Committee (DERC). Australian National University approval (reference 2016/500) was granted September 23, 2016. Analyses were carried out using SAS v9. 3 and StatsDirect v3. 0. 198.
Study characteristics A pool of 2,429 abstracts was screened and 82 articles were examined at the full-text stage. Of these, articles reporting on 27 studies were retained. Thirty-seven additional potential studies were identified from consortia and expert recommendation (figure e-1, doi. org/10. 5061/dryad. t9n4n3p). Of the 64 studies, 5 held no relevant data or indicated that data were no longer maintained  [16] [17] [18] [19] [20]  ; 27 studies  [7] [8] [9]  contributed data (table e-1, doi. org/10. 5061/dryad. t9n4n3p); and 2  studies did not participate. Reasons for nonparticipation included a lack of valid email contact or no response to inquiries and 4 declined to provide data. There were no evident differences in study design, proportion of study type, population, or region of recruitment between the studies that agreed and those that did not participate.
org/10. 5061/dryad. t9n4n3p). Mean baseline age in the sampled studies ranged from 57. 0  D ±5. 2)  24  to 93. 0 (SD ±2. 6)  26  years with the mean age of participants in the majority of participating studies  7, [21] [22] [23] 26, 27, 29, 31, 33, 37, [39] [40] [41] [42] [43]  in the range 70 to 79 years. Mean baseline systolic BP (SBP) was in the normotensive range (≤140 mm Hg) for 8 studies,  [21] [22] [23] [24] [25] [26] [44] [45] [46]  between 140 and 159 mm Hg for 13 studies,  8, [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] 43  and ≥160 mm Hg for 3 studies. 7, 9, 39  For 3 studies,  [40] [41] [42]  baseline BP was not available. Twenty-four studies  [7] [8] [9] [21] [22] [23] [25] [26] [27] [28] [29] [30] [31] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45]  contributed data on those aged >65 years at baseline, and 9  7, 8, 24, 25, 28, 32, 39, [44] [45] [46]  had some data on those aged ≤65 years at baseline.
Heterogeneity and publication bias Point estimates varied considerably in direction and magnitude per study (figures 1 and 2 and figures e-2 and e-3, doi. org/10. 5061/dryad. t9n4n3p). Heterogeneity in the metaanalyses ranged from 0% to 67. 7% (tables 1 and 2 and tables e-2 and e-3, doi. org/10. 5061/dryad. t9n4n3p), but publication bias measured by Egger test was only observed for BB compared to the untreated population for dementia in those with ≥1-year follow-up (p = 0. 0471) and for ACE-I compared to those with other antihypertensive treatment for dementia in those with ≥5 years of follow-up (p = 0. 0362). Overall, there were no consistent patterns for either dementia or cognitive decline outcomes.
Mortality and attrition by antihypertensive class Additional analyses were performed to assess whether there was an association between baseline AHM class and risk of death or dropout. OR for the outcomes death and dropout (combined) for the different AHM classes adjusted for age, sex, education, and baseline SBP or, where this was unavailable, for presence of hypertension at baseline, were as follows: diuretics, OR 0. 95 (95% CI 0. 79-1. 13); BB, OR 0. 98 (95% CI 0. 86-1. 12); CCB, OR 0. 93 (95% CI 0. 76-1. 13); ACE-I, OR 1. 04 (95% CI 0. 94-1. 16); and ARB, OR 0. 79 (95% CI 0. 63-1. 00). For some studies, data were available for either dropout or death but not both. Results did not change when the analyses were rerun excluding these studies.
org/10. 5061/dryad. t9n4n3p). However with ≥5 years of follow-up, AHM use was associated with a 35% lower risk of developing dementia in the fully adjusted pooled ratio (OR 0. 65; 95% CI 0. 51-0. 82), but the association was not statistically significant with the risk of incident cognitive decline (OR 0. 44; 95% CI 0. 15-1. 25). In those aged ≤65 years, 2 cohort studies were available to compare antihypertensive treatment with no treatment or placebo and could be combined for the outcome of dementia in those with ≥5 years of follow-up (pooled OR 0. 79; 95% CI, 0. 43-1. 48). Four cohorts were similarly pooled for the outcome of incident cognitive decline in those with ≥5 years of follow-up (pooled OR 1. 00; 95% CI 0. 60-1. 67) and 2 cohorts for cognitive decline in those with ≥1 year of follow-up (pooled OR 1.
Sensitivity analyses There were no clear patterns in findings or significant relationships by study type for those that were not trials of antihypertensives or when the OR of the participating study samples were plotted against decade of recruitment or percentage of female participants (appendix e-C, doi. org/10. 5061/dryad. t9n4n3p). Furthermore, rerunning the treated and untreated comparison by sex in those >65 years showed no differences for men and women (table e-9, doi. org/ 10. 5061/dryad. t9n4n3p).
Prospective longitudinal studies or trials of antihypertensives with data on antihypertensive class, a comparator group, and with a mean follow-up ≥1 year c Objective assessment of cognitive function on at least 2 occasions or assessment of dementia as an outcome using standard diagnostic or research criteria c Human studies Exclusion criteria c Non-English publications (in the absence of resources for translation) Studies solely using medical record databases c Studies in populations with cognitive impairment Data extraction, harmonization, and reduction in risk of bias Exposure to an antihypertensive medication (AHM) class was present if recorded over a minimum of a 12-month period, based on individual study records of antihypertensive drug use.
and figure1, and for ≥1-year follow-up, table e-2, doi. org/10. 5061/dryad. t9n4n3p; and figure e-2, doi. org/10. 5061/dryad. t9n4n3p; for full-size forest plots, see appendix e-B, doi. org/10. 5061/ dryad. t9n4n3p). Exposure to diuretics was associated with a statistically significant lower risk of incident dementia only Combined risk ratios for each antihypertensive class compared to no treatment or placebo for participants aged >65 years with ≥5 years follow-up.
cc Prospective longitudinal studies or trials of antihypertensives with data on antihypertensive class, a comparator group, and with a mean follow-up ≥1 year c Objective assessment of cognitive function on at least 2 occasions or assessment of dementia as an outcome using standard diagnostic or research criteria c Human studies Exclusion criteria c Non-English publications (in the absence of resources for translation) Studies solely using medical record databases c Studies in populations with cognitive impairment Data extraction, harmonization, and reduction in risk of bias Exposure to an antihypertensive medication (AHM) class was present if recorded over a minimum of a 12-month period, based on individual study records of antihypertensive drug use.
aAdjusted for sex, age, baseline systolic blood pressure, and education. Additional adjustment for ethnic group in the Einstein Aging Study. e270Neurology | Volume 94, Number 3 | January 21, 2020 Neurology. org/NAnadditional comparison between each antihypertensive class and those receiving any other antihypertensive treatment (cohort studies only) found no association between antihypertensive class, CCB, ACE-I, BB, ARB, or diuretic and risk of developing dementia in those with ≥5-year or ≥1-year followup (table2and table e-4, doi. org/10. 5061/dryad. t9n4n3p).
Mass spectrometry-based quantitative proteomic analysis Proteins were stacked in a single band in the top of an SDS-PAGE gel (4-12% NuPAGE, Life Technologies) and stained with Coomassie blue R-250 before in-gel digestion using modified trypsin (Promega, sequencing grade) as previously described  [52]. Resulting peptides were analyzed by online nanoliquid chromatography coupled to tandem MS (UltiMate 3000 and LTQ-Orbitrap Velos Pro, Thermo Scientific). Peptides were sampled on a 300 µm × 5 mm Pep-Map C18 precolumn (Thermo Scientific) and separated on a 75 µm × 250 mm C18 column (Reprosil-Pur 120 C18-AQ, 3 μm, Dr. Maisch) using a 120 min gradient. MS and MS/ MS data were acquired using Xcalibur (Thermo Scientific). Peptides and proteins were identified and quantified using Mascot (version 2.
6. 0) using the Uniprot database (Mus musculus taxonomy) and the frequently observed contaminant database embedded in MaxQuant. Trypsin was chosen as the enzyme and two missed cleavages were allowed. Peptide modifications allowed during the search were: carbamidomethylation (C, fixed), acetyl (Protein N-ter, variable), and oxidation (M, variable). The Proline software  [6]  was used to filter the results: conservation of rank 1 peptides, peptide score ≥ 25, peptide length ≥ 6, peptide-spectrummatch identification false discovery rate < 1% as calculated on scores by employing the reverse database strategy, and minimum of 1 specific peptide per identified protein group. Proline was then used to perform a compilation, grouping, and MS1 quantification of the protein groups using specific peptides.
Statistical analysis was performed using ProStaR  [68]. Proteins identified in the reverse and contaminant databases, proteins only identified by site, proteins identified by MS/MS in less than two replicates in one condition, and proteins exhibiting less than four intensity values in one condition were discarded from the list. After log2 transformation, abundance values were normalized using the variance stabilizing normalization procedure before missing value imputation (slsa method for partially observed values and DetQuantile with quantile and factor set to 1 for values missing in the entire condition); statistical testing was conducted using limma test. Differentially expressed proteins were sorted out using a log2 (fold change) cut-off of 0. 8 and a p value cut-off inferior to 0. 05 (allowing to reach a Benjamini-Hochberg FDR inferior to 5%).
SDS-PAGE Western blotting was then performed and membranes were cut into strips to detect several proteins (IP3R1, VDAC, and Grp75) at the same time. Phospho-AKT, AKT, CHOP, and Grp78 proteins were detected in total heart homogenates (50 µg), phospho-PDH, and PDH proteins were assessed in cardiomyocyte lysates (30 µg), while MICU1 and MCU proteins were detected in pure mitochondria samples (15 µg). Mfn2 and VDAC assessments were done on isolated cardiac MAM samples (15 µg). After sample loading, proteins were transferred onto a nitrocellulose membrane, which was blocked for 1 h with 5% bovine serum albumin (BSA)-PBS. Immunoblotting was performed by incubating the membranes overnight at 4 °C with primary antibodies: rabbit anti-IP3R1 (1/1000; sc28614), mouse anti-VDAC (1/1000; Abcam, ab14734), mouse anti-Grp75 (1/1000; sc133137), rabbit anti-phospho-AKT (1/1000; Cell Signaling 4060L), rabbit anti-AKT (1/1000; Cell Signaling 4691S), mouse anti-CHOP (1/1000; Cell Signaling 2895S), goat anti-Grp78 (1/500; sc1050), rabbit anti-MICU1 (1/500; Sigma HPA037480), rabbit anti-MCU (1/1000; Sigma HPA016480), rabbit anti-MFN2 (1/1000; Abcam ab50838), mouse anti-phospho-PDH (1/2000; Cell Signaling 31866S), and rabbit anti-PDH (1/000; Cell Signaling C54G1) prepared in 5% BSA-PBS.
Horseradish peroxidase-conjugated anti-mouse and antirabbit secondary antibodies (1/10,000; Biorad) were added for 1 h incubation at RT. Immunoblot development was done using the reaction substrate ECL prime reagent (GE healthcare) with Bio-Rad Molecular Imager Gel Doc XR + (Bio-Rad). Image Lab software (Bio-Rad) was used for quantification.
). Transient peaks and minima were detected with a standard algorithm for finding local extrema based on the derivative of the signal and the corresponding amplitude and time of each extremum were recorded. From these values, different parameters were measured: time to peak, half-time, and time peak to basal. Cardiomyocyte shortening was evaluated in Fluo-4 loaded cells by line scanning along the long axis. Cell length was measured, using ImageJ software, in the resting state and in the maximally contracted state to express the shortening as a percentage of the resting cell length.
Echocardiography Echocardiography was performed under a light anesthesia (ketamine 80 mg/kg ip), with a digital ultrasound system (Vivid 7, GE Medical Systems) and a 13-MHz linear-array transducer as previously described  [61]. LV end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), fractional shortening (FS), anterior wall thickness (AWT), and posterior wall thickness (PWT) were obtained from M-mode tracings at the level of the papillary muscles. LV mass was calculated using the following formula: 1. 05 × [ ( AWT + PWT + LVEDD)3 -LVEDD3]  [37, 48]. Strain-rate images were obtained from the parasternal short-axis views at the midventricular level as previously described  [56, 60]. Echography analyses were performed offline by an observer blinded to the groups with the use of the EchoPac Software (GE Medical).
Statistical analysis Parametric t test and one-way ANOVA were performed for statistical analysis of echocardiography measurements (from the table), after validation of the Shapiro-Wilk normality test: these data are presented as mean ± SEM. For all the other analyses, non-parametric tests were used: Mann-Whitney test for two groups, Kruskal-Wallis test followed by the Dunn's multiple comparisons test for three groups as a one-way ANOVA with only one variable, whereas for two variables, a two-way ANOVA followed by a Sidak or a Tukey's post hoc test were applied. Data are thus expressed as median (interquartile range: P  [25] , P[75]). Experiments were performed at least in three different mice per group (= N), with the two (SD, HFHSD) or three groups (SD, HFHSD, HFHSD/SD) each day. For single-cell imaging analysis, statistics were performed on n = number of cells to assess single-cell effect as well as heterogeneity between them.
2c ). The Volcano plot of the cardiac MAM proteome visually highlights that 14 proteins were significantly ≥ 1. 75 times upregulated and 15 proteins ≥ 1. 75 times downregulated compared to the SD group (Fig. 2f , Supplementary Table  1 ). Functional annotation of MAM proteins was performed using the Panther software, revealing an upregulation of lipid metabolic and response to stress processes in the HFHSD model compared to SD (Fig. 2g , Supplementary Table  2 ). On the other hand, ATP metabolic process, protein/ ion transport, and cation homeostasis were downregulated in the HFHSD cardiac MAM. A significant decrease in the protein expression of the known MAM-tethering protein MFN2 was also observed in the HFHSD cardiac MAM (Fig. 2h ). However, proteomic analysis revealed no significant changes in VDAC1, Grp75, RyR2, and Serca2 expression in the HFHSD MAM (Supplementary Table  1 ).
Acknowledgements We would like to thank  Dr Etienne Lefai  ( Unité de nutrition humaine, Clermont-Ferrand ) and  Jingwei Ji-cao  ( INSERM U11060, Lyon ) for their technical expertise on adenovirus construction and TG quantification,  Dr Yves Gouriou  and  Dr Bruno Pillot  (both of  INSERM U11060, Lyon ) for their precious advice, respectively, on Ca 2+ imaging and ethics, and  Elisabeth Errazuriz ,  Christel Cassin  et  Annabelle Bouchardon  at the  CIQLE platform (Lyon, France ) for the EM and histology preparation and help on the analysis.
Funding The study was founded by a grant from Fondation de France (n 00056853) to MP and JR, by a contribution from the Azm and Saade association, and supported by Fondation Leducq as part of its RETP equipment program and TNE program (n 16CVD04: Mitocardia Network) to MO. MP was a recipient of postdoctoral fellowships from the Fondation Lefoulon-Delalande and Fondation pour la Recherche Médicale (n ARF20160936149). JR is involved in the CARDIATEAM project, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821508. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. MO was supported by the OPeRa (ANR-10-IBHU-0004 OPeRa) and the RHU MARVELOUS (ANR-16-RHUS-0009) programs.
Results and discussion Frequent horizontal transfers of transposable elements. We investigated HTT involving most TE types among 307 vertebrate species whose genome sequences are publicly available on Gen-Bank (Supplementary Data 1), following principles developed in earlier studies  18, 24. To avoid detection biases that could have arisen from the use of available TE databases of varying quality across species, TEs were de novo characterized with the same procedure for all genomes. Consensus sequences (Supplementary Data 2) were built with the RepeatModeler pipeline  30  and TE copies were annotated using RepeatMasker  31. We excluded elements that might contain genes coding for proteins that were not listed in TE protein databases, as a result of erroneous TE superfamily assessment. More than 133 million TE copies ≥ 300 base pairs (bp) belonging to diverse superfamilies of retrotransposons and DNA transposons were extracted from all genomes (Supplementary Data 3).
Methods Source data. We used 307 vertebrate genome sequences whose accession numbers are provided in Supplementary Data 1. These sequences constitute the set that was available on GenBank as of December 2017, excluding 13 species whose genome sequence was considered too short or of insufficient quality. We built a timetree of these taxa (Supplementary Data 5) using timetree. org  54. Most of the following analyses were automated via custom scripts written in R  55. Transposable element annotation and similarity search. The de novo annotation of TEs via RepeatModeler v. 1. 0. 10 30 used the parameter "ncbi" as search engine to generate TE family consensus sequences. We excluded consensuses presenting non-TE genes  24  by performing blastx searches of consensus sequences against the non-redundant database of proteins from NCBI.
These searches used Diamond v. 0. 9. 19  56. We also excluded TEs recognized as Short Interspersed Nuclear Elements (SINEs), which do not contain protein-coding regions required for Ka and Ks computations  24. Remaining consensuses that were assigned to defined TE superfamilies (i. e. , characterized below the level of TE subclass) were used to locate TE copies in each genome with the RepeatMasker program v. 4. 0. 7  31  , ignoring low complexity regions. Copies were extracted from contigs/scaffolds with seqtk v. 1. 2-r94 (https://github. com/lh3/seqtk). All blast searches used ncbi blast version 2. 6. 0+  32. For every relevant pair of genomes, we performed reciprocal blastn searches between TE copies of at least 300 bp, reporting only the best alignment per query sequence per search  24.
We retained alignments of at least 300 bp in length, with sequence identity ≥75%, quality score ≥200 and between TEs assigned to the same superfamily. This last criterion was fulfilled by ~98% of the hits passing the three previous ones, indicating that the automatic TE classification was generally accurate. Estimating synonymous and non-synonymous TE mutation rates. Ka and Ks rates were computed on homologous regions of pairs of TE copies, for different stages of this analysis (see next subsections). This computation required delineating protein-coding regions in these TEs. This was achieved through successive similarity searches  24  with Diamond 56 , of TEs copies against the database of TE proteins used by RepeatModeler. More than 99% of the blastx hits involved a TE and a protein assigned to the same superfamily, again supporting the accuracy of the TE classification.
The remaining <1% of hits between a TE and a protein of different superfamilies were discarded. Homologous TE regions of a TE-TE hit, as reported by blastn, were extracted from TE copy sequences with seqtk and realigned using the Biostrings R package v. 2. 52  57. Every aligned base in each TE copy was attributed a position within a codon based on the Diamond blastx alignment coordinates of TE copies on proteins. Nucleotides of undetermined or mismatched within-codon positions between copies were deleted, so were indels and resulting truncated codons. On the remaining codons, Ka-Ks rates were computed with Li's method  58  implemented in the seqinr R package v. 3. 4-5  59. This procedure effectively reconstructs (partial) homologous protein-coding sequences from a pair of TEs. Selecting TE similarities resulting from HTT.
Core genes were annotated from the genome sequences by the BUSCO v. 3. 0. 1 pipeline  60  , using the database of single-copy proteins that was the most relevant for each vertebrate group. Our aim was to generate core-gene Ks distributions for every pair of sister clades, as done in recent studies  24, 25. Each distribution therefore represents the degree of neutral molecular divergence between two lineages more accurately than a distribution based on a single species pair. This approach also allows using species that have few annotated genes (for instance, no core gene could be annotated for the collared flycatcher Ficedula albicollis). To reduce the workload, Ks distributions involving two sister clades older than 250 My used just one genome per subclade younger than 30 My, the one with the highest number of annotated core genes.
Sequence identities between TE copies of the same clade were obtained through blastn searches of all copies of a superfamily (those in the retained hits) against themselves, without restriction on the number of results per query, but discarding alignments shorter than 100 bp. Any two hits passing criterion 1 were "connected", resulting in an undirected graph of hits, within which groups of hits (hereafter called "communities" to avoid confusion between iterations) were delineated by the clustering algorithm  61  implemented in the igraph R package v. 1. 2. 4. 1. In the second iteration, we generated pairs of communities to evaluate if hits composing the two communities of a pair could result from a single HTT event, this time by applying both criterion 1 and our newly-developed criterion ("criterion 2") that compares the degree of divergence of species to that of TE copies (Fig.