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Objective: To generate a national multiple sclerosis (MS) prevalence estimate for the United States by applying a validated algorithm to multiple administrative health claims (AHC) datasets. Methods: A validated algorithm was applied to private, military, and public AHC datasets to identify adult cases of MS between 2008 and 2010. In each dataset, we determined the 3-year cumulative prevalence overall and stratified by age, sex, and census region. We applied insurance-specific and stratum-specific estimates to the 2010 US Census data and pooled the findings to calculate the 2010 prevalence of MS in the United States cumulated over 3 years. We also estimated the 2010 prevalence cumulated over 10 years using 2 models and extrapolated our estimate to 2017. Results: The estimated 2010 prevalence of MS in the US adult population cumulated over 10 years was 309.2 per 100,000 (95% confidence interval [CI] 308.1–310.1), representing 727,344 cases. During the same time period, the MS prevalence was 450.1 per 100,000 (95% CI 448.1–451.6) for women and 159.7 (95% CI 158.7–160.6) for men (female:male ratio 2.8). The estimated 2010 prevalence of MS was highest in the 55- to 64-year age group. A US north-south decreasing prevalence gradient was identified. The estimated MS prevalence is also presented for 2017. Conclusion: The estimated US national MS prevalence for 2010 is the highest reported to date and provides evidence that the north-south gradient persists. Our rigorous algorithm-based approach to estimating prevalence is efficient and has the potential to be used for other chronic neurologic conditions. Prev of MS in the US-E-Appendix-Feb-19-2018

Web Supplementary Files Web Supplementary File 1 - FASTA files containing full-length reconstruction input sequences: full_length_reconstruction_input_sequence_fastas.zip Web Supplementary File 2 - FASTA files containing Muscle alignments of the full-length reconstruction input sequences. full_length_reconstruction_input_sequence_alns.zip Web Supplementary File 3 - FASTA file of full-length reconstructed sequences: full_length_reconstructions.fa Web Supplementary File 4 - Table of full-length reconstruction statistics: full_length_reconstruction_stats.csv Web Supplementary File 5 - FASTA files containing ORF reconstruction input sequences: orf_fastas.zip Web Supplementary File 6 - FASTA files containing Macse alignments of the ORF reconstruction input sequences: ORF_reconstruction_input_sequence_alns.zip Web Supplementary File 7 - Table of ORF reconstruction statistics: ORF_reconstructions.fa Web Supplementary File 8 - Table of ORF reconstruction statistics: ORF_reconstruction_stats.csv Web Supplementary File 9 - Table of Composite Sequences: bestfl_selection_fixed_CS_seqs.csv Web Supplementary File 10 - Database of gold standards: L1_goldstandards.csv Data Underlying Figures RepeatMasker scans of hg38 and ancestral genomes: anc_gen_RM_out_files.zip Figure 4 4A Source alignment of 54 composite sequences: 220121_dropped12+L1ME3A_muscle.nt.afa Tree produced using the alignment and FastTree: 220121_dropped12+L1ME3A.tree 4B Source alignment of 67 Dfam L1 subfamily 3’ end models: 200123_dfam_3ends.fa.muscle.aln Tree produced using the alignment: 200123_dfam_3ends.fa.muscle.aln.tree Figure 5 KZFP-TE enrichment p-values (from Barazandeh et al 2018): TE_KZFP_enrichment_pvals.xlsx KZFP-TE top 500 peak overlap (from Barazandeh et al 2018): top500_peak_overlap.xlsx Figure 6 RepeatMasker .out file for the Composite Sequence custom library queried against hg38: CS_RM_hg38.fa.out.gz Figure S2 RepeatMasker scan .out file of hg38 (CG corrected Kimura Divergence values are in last column): hg38+KimDiv_RM.out RepeatMasker scan .out file of the Progressive Cactus eutherian ancestral genome (CG corrected Kimura Divergence values are in last column): Progressive_Cactus_Euth+KimDiv_RM.out RepeatMasker scan .out file of the Ancestors 1.1 eutherian ancestral genome (CG corrected Kimura Divergence values are in last column): Ancestors_Euth+KimDiv_RM.out Figure S5 RepeatMasker scan .out files for Progressive Cactus simian and primate reconstructed ancestral genomes: progCactus_RM_outfiles.zip S5A FASTA files containing Cactus genome-derived reconstructed sequences equivalent to the L1MA2, L1MA4, and L1MD1-3 best full-length sequences: progCactus_reconstruction_bestFL_equivalents.zip S5B FASTA files containing Muscle alignments of Cactus genome-derived full-length reconstruction input sequences: progCactus_reconstruction_input_sequence_alns.zip Figure S6 S6A Results of Conserved Domain scans of Cactus genome-derived full-length reconstructed sequences: CD_search_results_short_nms.txt S6B-D Character posterior probabilities of “best” full-length reconstructed sequences: best_fl_post_probs.zip Figure S7 S7B-C Results of Conserved Domain scans of translated initial full-length reconstructed sequences: initial_recons_all_3frametrans_CD-search.txt Results of Conserved Domain scans of translated reconstructed ORFs: recons_ORF1-2_all_3frametrans_CD-search.csv Figure S15 S15A Source alignment of 67 composite sequences: bestfl_selection_fixed_CS_seqs_muscle.nt.afa Tree produced using the alignment: bestfl_selection_fixed_CS_seqs_muscle.nt.afa.tree S15B-E Source Muscle alignments for phylogenetic trees of reconstructed sequence components: ORF2: ORF2_keep54_muscle.nt.afa 5’ UTR: 5utr_keep54_muscle.nt.afa ORF1: ORF1_keep54_muscle.nt.afa 3’ UTR: 3utr_keep54_muscle.nt.afa Trees produced using above alignments: ORF2: ORF2_keep54_muscle.nt.afa.tree 5’ UTR: 5utr_keep54_muscle.nt.afa.tree ORF1: ORF1_keep54_muscle.nt.afa.tree 3’ UTR: 3utr_keep54_muscle.nt.afa.tree Figure S17 Unfiltered BLAST results of Composite Sequences queried against hg38: CS_hg38_blastn.csv.zip BED file of L1 instances annotated using BLAST pipeline: BLAST_L1_hits.bed

OBJECTIVE. To assess whether HS severity is mirrored at the level of large-scale networks. METHODS. We studied preoperative high-resolution anatomical and diffusion-weighted MRI of 44 TLE patients with histopathological diagnosis of HS (n=25; TLE-HS) and isolated gliosis (n=19; TLE-G), and 25 healthy controls. Hippocampal measurements included surface-based subfield mapping of atrophy and T2 hyperintensity indexing cell loss and gliosis, respectively. Whole-brain connectomes were generated via diffusion tractography and examined using graph theory along with a novel network control theory paradigm which simulates functional dynamics from structural network data. RESULTS. Compared to controls, we observed markedly increased path length and decreased clustering in TLE-HS compared to controls, indicating lower global and local network efficiency, while TLE-G showed only subtle alterations. Similarly, network controllability was lower in TLE-HS only, suggesting limited range of functional dynamics. Hippocampal imaging markers were positively associated with macroscale network alterations, particularly in ipsilateral CA1-3. Systematic assessment across several networks revealed maximal changes in the hippocampal circuity. Findings were consistent when correcting for cortical thickness, suggesting independence from grey matter atrophy. CONCLUSIONS. Severe HS is associated with marked remodeling of connectome topology and structurally-governed functional dynamics in TLE, as opposed to isolated gliosis which has negligible effects. Cell loss, particularly in CA1-3, may exert a cascading effect on brain-wide connectomes, underlining coupled disease processes across multiple scales. Data_phen_conn_dryadPhenotypic information and mean connectome feature data for Bernhardt et al. (2019) Temporal lobe epilepsy: hippocampal pathology modulates white matter connectome topology and controllability. Neurology

Living in permanent social groups forces animals to make decisions about when, how and with whom to interact, requiring decisions to be made that integrate multiple sources of information. Changing social environments can influence this decision-making process by constraining choice or altering the likelihood of a positive outcome. Here, we conceptualised grooming as a choice situation where an individual chooses one of a number of potential partners. Studying two wild populations of sympatric primate species, sooty mangabeys (Cercocebus atys atys) and Western chimpanzees (Pan troglodytes verus), we tested what properties of potential partners influenced grooming decisions, including their relative value based on available alternatives and the social relationships of potential partners with bystanders who could observe the outcome of the decision. Across 1,529 decision events, multiple partner attributes (e.g. dominance ranks, social relationship quality, reproductive state, partner sex) influenced choice. Individuals preferred to initiate grooming with partners of similar global rank, but this effect was driven by a bias towards partners with a high rank compared to other locally available options. Individuals also avoided grooming partners who had strong social relationships with at least one bystander. Results indicated flexible decision-making in grooming interactions in both species, based on a partner’s value given the local social environment. Viewing partner choice as a value-based decision-making process allows researchers to compare how different species solve similar social problems. Data Model1Data for Models 1-1 and 1-2Data Model2Data for Models 2-1 and 2-2Script Model 1 and 2Scripts necessary to analyse Models 1 and 2

Supplementary File 1: R Code and output - Demographic AnalysisThis is a stand alone report containing the code and output of an R script, which was generated by the "Compile Report" function in RStudio (R Statistical Software package (version 3.2.4 (2016-03-10))). This code summarizes the demographic, obstetric, and sleep behaviour of the participants (collected via a questionnaire completed by each participant on her first sleep test) and compares these data between all participants whose first sleep test was PrenaBelt (followed by sham-PrenaBelt on the second sleep test) versus all participants whose first sleep test was sham-PrenaBelt (followed by PrenaBelt on the second sleep test).Code and output - Demographic Analysis.docxSupplementary File 2: R Code and output - PSG AnalysisThis is a stand alone report containing the code and output of an R script, which was generated by the "Compile Report" function in RStudio (R Statistical Software package (version 3.2.4 (2016-03-10))). This code processes the polysomnography (PSG) sleep reports in full, making within-participant (paired) comparisons and between-participant (unpaired) comparisons. The sleep reports were generated by Embla Sandman Elite sleep diagnostic software (Natus Medical Incorporated, Pleasanton, USA). The data in the PSG sleep reports was collected via Pro-Tech zRIP Durabelts (Philips Respironics, Murrysville, USA) for respiration, PT1 pressure transducers (BRAEBON Medical Corporation, Kanata, Canada) for airflow and snoring, electrodes (Natus Medical Incorporated, Pleasanton, USA) for ECG/EEG/EOG/EMG, and finger-tip pulse oximetry for peripheral blood oxygen saturation (SpO2) in accordance with the American Academy of Sleep Medicine 2014 guidelines. Audio and video data were also recorded and used in order to determine body position and snoring.Code and output - PSG Analysis.docxSupplementary File 3: R Code and output - Feedback AnalysisThis is a stand alone report containing the code and output of an R script, which was generated by the "Compile Report" function in RStudio (R Statistical Software package (version 3.2.4 (2016-03-10))). This code processes the participants' feedback on the PrenaBelt (collected via a questionnaire completed by each participant after each sleep test). It summarizes these data, completes within-participant (paired) comparison of these data ("before/after"), and completes between-participants (unpaired) comparison of these data (bulk test for differences between all PrenaBelt sleep test nights versus all sham-PrenaBelt nights).Code and output - Feedback Analysis.docxSupplementary File 4: R Code and output - Self-Report Accuracy AnalysisThis is a stand alone report containing the code and output of an R script, which was generated by the "Compile Report" function in RStudio (R Statistical Software package (version 3.2.4 (2016-03-10))). This code compares each participant's perception of her sleep behaviours (collected via a questionnaire completed by each participant after each sleep test) to her polysomnography-determined sleep behaviours (collected via audio and video and Embla Sandman Elite sleep diagnostic software (Natus Medical Incorporated, Pleasanton, USA)) in order to determine the ability of participants to accurately recall their sleep onset position, waking position, number of position changes during the night, and percentage of sleep time in each position.Code and output - Self-Report Accuracy Analysis.docx OBJECTIVE: To evaluate whether the percentage of time spent supine during sleep in the third trimester of pregnancy could be reduced using a positional therapy device (PrenaBelt) compared with a sham device. DESIGN: A double-blind, randomized, sham-controlled, crossover pilot trial. SETTING: Conducted between March 2016 and January 2017, at a single, tertiary-level center in Canada. PARTICIPANTS: Twenty-three participants entered the study. Twenty participants completed the study. Participants were low-risk, singleton, third-trimester pregnant women aged 18 years and older with BMI <35 at the first antenatal appointment for the index pregnancy and without known fetal abnormalities, pregnancy complications, or medical conditions complicating sleep. INTERVENTIONS: A two-night, polysomnography study in a sleep laboratory. Participants were randomized by computer-generated, one-to-one, simple randomization to receive either a the PrenaBelt or a sham-PrenaBelt on the 1st night and were crossed over to the alternate device on the 2nd night. Allocation concealment was by unmarked, security-tinted, sealed envelopes. Participants, the recruiter, and personnel involved in setting up, conducting, scoring, and interpreting the polysomnogram were blinded to allocation. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the percentage of time spent supine during sleep. Secondary outcomes included maternal sleep architecture, respiration, self-reported sleep position, and feedback. RESULTS: The median percentage of sleep time supine was reduced from 16.4% on the sham night to 3.5% on the PrenaBelt night (pseudomedian=5.8, p=0.03). We were unable to demonstrate differences in sleep architecture or respiration. Participants underestimated the time they spent sleeping supine by 7.0%, and six (30%) participants indicated they would make changes to the PrenaBelt. There were no harms in this study. CONCLUSIONS: This study demonstrates that the percentage of sleep time supine during late pregnancy can be significantly reduced via positional therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02377817

Objectives: Degenerative cervical myelopathy (DCM) involves extrinsic spinal cord compression causing tissue injury and neurological dysfunction. Asymptomatic spinal cord compression (ASCC) is more common but its significance is poorly defined. This study investigates if: 1) ASCC can be automatically diagnosed using spinal cord shape analysis; 2) multiparametric quantitative MRI can detect similar spinal cord tissue injury as previously observed in DCM. Design: Prospective observational longitudinal cohort study. Setting: Single centre, tertiary care and research institution. Participants: 40 neurologically intact subjects (19 female, 21 male) divided into groups with and without ASCC. Interventions: None. Outcome Measures: Clinical assessments: modified Japanese Orthopedic Association (mJOA) score and physical examination. 3T MRI assessments: automated morphometric analysis compared with consensus ratings of spinal cord compression, and measures of tissue injury: cross-sectional area (CSA), diffusion fractional anisotropy (FA), magnetization transfer ratio (MTR), and T2-weighted imaging white to grey matter signal intensity ratio (T2WI WM/GM) extracted from rostral (C1-3), caudal (C6-7), and maximally compressed levels (MCL). Results: ASCC was present in 20/40 subjects. Diagnosis with automated shape analysis showed area under the curve > 97%. Five MRI metrics showed differences suggestive of tissue injury in ASCC compared with uncompressed subjects (p<0.05), while a composite of all 10 measures (average of z scores) showed highly significant differences (p=0.002). At follow-up (median 21 months), two ASCC subjects developed DCM. Conclusions: ASCC appears to be common and can be accurately and objectively diagnosed with automated morphometric analysis. Quantitative MRI appears to detect subclinical tissue injury in ASCC prior to the onset of neurological symptoms and signs. These findings require further validation, but offer the intriguing possibility of pre-symptomatic diagnosis and treatment of DCM and other spinal pathologies. Registration: Not registered. Demographic, morphometric, and quantitative MRI dataData includes anonymized subject ID, presence of spinal cord compression, age, sex, follow-up mJOA score, spinal cord morphometric parameters of compression ratio, solidity, and relative rotation, measured at C2-3, C3-4, C4-5, C5-6, and C6-7, and quantitative MRI measures of cross sectional area, magnetization transfer ratio, fractional anisotropy, and T2*-weighted white matter to grey matter signal intensity ratio, measured at rostral (C1-3), maximally compressed level, and caudal (C6-7) levels.qMRI_subclinical_tissue_injury_public_data.xlsx

We carried out an admixture mapping study of lipid traits in two samples from Mexico City. Native American locus ancestry was significantly associated with triglyceride levels in a broad region of chromosome 11 overlapping the BUD13, ZNF259 and APOA5 genes. In our fine-mapping analysis of this region using dense genome-wide data, rs964184 is the only marker included in the 99% credible set of SNPs, providing strong support for rs964184 as the causal variant within this region. The frequency of the allele associated with increased triglyceride concentrations (rs964184-G) is between 30-40% higher in Native American populations from Mexico than in European populations. The evidence currently available for this variant indicates that it may be exerting its effect through three potential mechanisms: 1) modification of enhancer activity, 2) regulation of the expression of several genes in cis and/or trans, or 3) modification of the methylation patterns of the promoter of the APOA5 gene. MC-sample1-HDL-AMAdmixture Mapping results for HDL-cholesterol: Mexico City sample 1MC-sample1-LDL-AMAdmixture Mapping results for LDL-cholesterol: Mexico City sample 1MC-sample1-TCHOL-AMAdmixture Mapping results for Total-cholesterol: Mexico City sample 1MC-sample1-TG-AMAdmixture Mapping results for triglycerides: Mexico City sample 1MC-sample2-HDL-AMAdmixture Mapping results for HDL-cholesterol: Mexico City sample 2MC-sample2-LDL-AMAdmixture Mapping results for LDL-cholesterol: Mexico City sample 2MC-sample2-TCHOL-AMAdmixture Mapping results for Total-cholesterol: Mexico City sample 2MC-sample2-TG-AMAdmixture Mapping results for triglycerides: Mexico City sample 2Mexico-City-AM-signalsAdmixture Mapping signals identified in both Mexico City samples for all the lipid traits.

Many anaerobic microbial parasites possess highly modified mitochondria known as mitochondrion-related organelles (MROs). The best-studied of these are the hydrogenosomes of Trichomonas vaginalis and Spironucleus salmonicida, which produce ATP anaerobically through substrate-level phosphorylation with concomitant hydrogen production; and the mitosomes of Giardia intestinalis, which are functionally reduced and lack any role in ATP production. However, to understand the metabolic specializations that these MROs underwent in adaptation to parasitism, data from their free-living relatives are needed. Here, we present a large-scale comparative transcriptomic study of MROs across a major eukaryotic group, Metamonada, examining lineage-specific gain and loss of metabolic functions in the MROs of Trichomonas, Giardia, Spironucleus and their free-living relatives. Our analyses uncover a complex history of ATP production machinery in diplomonads such as Giardia, and their closest relative, Dysnectes; and a correlation between the glycine cleavage machinery and lifestyles. Our data further suggest the existence of a previously undescribed biochemical class of MRO that generates hydrogen but is incapable of ATP synthesis. Protein alignmentsAlignments of organellar proteinsmito_alignments.zipPhylogenomic datasetSingle gene alignments used for phylogenomic analysisPhylogenomic.zipData SourcesFasta files with assembled transcriptomes of Carpediemonas-like organismsAssemblies.zip

Microglia respond to CNS injuries and diseases with complex reactions, often called “activation.” A pro-inflammatory phenotype (also called classical or M1 activation) lies at one extreme of the reactivity spectrum. There were several motivations for this study. First, bacterial endotoxin (lipopolysaccharide, LPS) is the most commonly used pro-inflammatory stimulus for microglia, both in vitro and in vivo; however, pro-inflammatory cytokines (e.g., IFNγ, TNFα) rather than LPS will be encountered with sterile CNS damage and disease. We lack direct comparisons of responses between LPS and such cytokines. Second, while transcriptional profiling is providing substantial data on microglial responses to LPS, these studies mainly use mouse cells and models, and there is increasing evidence that responses of rat microglia can differ. Third, the cytokine milieu is dynamic after acute CNS damage, and an important question in microglial biology is: How malleable are their responses? There are very few studies of effects of resolving cytokines, particularly for rat microglia, and much of the work has focused on pro-inflammatory outcomes. Here, we first exposed primary rat microglia to LPS or to IFNγ+TNFα (I+T) and compared hallmark functional (nitric oxide production, migration) and molecular responses (almost 100 genes), including surface receptors that can be considered part of the sensome. Protein changes for exemplary molecules were also quantified: ARG1, CD206/MRC1, COX-2, iNOS, and PYK2. Despite some similarities, there were notable differences in responses to LPS and I+T. For instance, LPS often evoked higher pro-inflammatory gene expression and also increased several anti-inflammatory genes. Second, we compared the ability of two anti-inflammatory, resolving cytokines (IL-4, IL-10), to counteract responses to LPS and I+T. IL-4 was more effective after I+T than after LPS, and IL-10 was surprisingly ineffective after either stimulus. These results should prove useful in modeling microglial reactivity in vitro; and comparing transcriptional responses to sterile CNS inflammation in vivo. Lively & Schlichter_6h_24h NanoString count dataNormalized mRNA counts

Microtubules are cytoskeletal structures involved in stability, transport and organization in the cell. The building blocks, the α- and β-tubulin heterodimers, form protofilaments that associate laterally into the hollow microtubule. Microtubule also exists as highly stable doublet microtubules in the cilia where stability is needed for ciliary beating and function. The doublet microtubule maintains its stability through interactions at its inner and outer junctions where its A- and B-tubules meet. Here, using cryo-electron microscopy, bioinformatics and mass spectrometry of the doublets of Chlamydomonas reinhardtii and Tetrahymena thermophila, we identified two new inner junction proteins, FAP276 and FAP106, and an inner junction-associated protein, FAP126, thus presenting the complete answer to the inner junction identity and localization. Our structural study of the doublets shows that the inner junction serves as an interaction hub that involves tubulin post-translational modifications. These interactions contribute to the stability of the doublet and hence, normal ciliary motility. Cilia were purified from Chlamydomonas, salt-treated to remove outside proteins. The samples were subjected to tandem mass spectrometry according to the protocol described in Dai et al. 2019, bioRxiv. (https://doi.org/10.1101/739383)