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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

Collections of cells called engrams are thought to represent memories. Although there has been progress in identifying and manipulating single engrams, little is known about how multiple engrams interact to influence memory. In lateral amygdala (LA), neurons with increased excitability during training outcompete their neighbors for allocation to an engram. We examined whether competition based on neuronal excitability also governs the interaction between engrams. Mice received two distinct fear conditioning events separated by different intervals. LA neuron excitability was optogenetically manipulated and revealed a transient competitive process that integrates memories for events occurring closely in time (coallocating overlapping populations of neurons to both engrams) and separates memories for events occurring at distal times (disallocating nonoverlapping populations to each engram). Rashid et al Science 2016- Data for Figs 1-4, S1-S9Excel file with all data presented in manuscript (each sheet corresponds to specific figures as indicated).Rashid et al Science 2016.xlsx

Premise of the study: Polyploidization is a common and recurring phenomenon in plants and is often thought to be a mechanism of "instant speciation." Whether polyploidization is associated with the formation of new species ("cladogenesis") or simply occurs over time within a lineage ("anagenesis") has never, however, been assessed systematically. Methods: Here, we tested this hypothesis using phylogenetic and karyotypic information from 235 plant genera (mostly angiosperms). We first constructed a large database of combined sequence and chromosome number data sets using an automated procedure. We then applied likelihood models (ClaSSE) that estimate the degree of synchronization between polyploidization and speciation events in maximum likelihood and Bayesian frameworks. Key results: Our maximum likelihood analysis indicated that 35 genera supported a model that includes cladogenetic transitions over a model with only anagenetic transitions, whereas three genera supported a model that incorporates anagenetic transitions over one with only cladogenetic transitions. Furthermore, the Bayesian analysis supported a preponderance of cladogenetic change in four genera but did not support a preponderance of anagenetic change in any genus. Conclusions: Overall, these phylogenetic analyses provide the first broad confirmation that polyploidization is temporally associated with speciation events, suggesting that it is indeed a major speciation mechanism in plants, at least in some genera. PloiDBPhylogenetic trees inferred using MrBayes, ploidy estimates using ChromEvol, and TPL-based genus species diversity estimates for 223 genera.ploidb_dryad.tar.gz

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

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

Query strain identities and corresponding screening set.In order to obtain an IDTS-wide genetic interaction map, we modified the automated, high-density replica plating approaches previously developed for analyzing S. cerevisiae double mutants through Synthetic Genetic Array (SGA) analysis (Tong AH, Evangelista M, Parsons AB, Xu H, Bader GD, Page N, Robinson M, Raghibizadeh S, Hogue CW, Bussey H, Andrews B, Tyers M, Boone C (2001) Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 294: 2364-2368). Instead of looking at double mutants, however, we used yeast genetics to systematically assess the effects of Legionella effector co-expression on yeast growth. Query strains that express one effector were mated to an array of ~330 effectors in groups of ~10 queries at a time ("Analysis Set"). The arrays were then imaged using a high-resolution camera and the spot sizes were quantified using SGAtools (http://sgatools.ccbr.utoronto.ca/) (Wagih O, Usaj M, Baryshnikova A, VanderSluis B, Kuzmin E, Costanzo M, Myers CL, Andrews BJ, Boone CM, Parts L (2013) SGAtools: One-stop analysis and visualization of array-based genetic interaction screens. Nucleic acids research 41: W591-596). Outlier spot sizes flagged by the Jackknife filter (JK) in SGAtools were removed and the average and standard deviation of the remaining values were calculated and normalized to the average empty vector control. This spreadsheet lists all query strains and links them to one or more specific analysis set.Array_set_annotation.xlsSGA output for analysis sets 1-10.Query strains that express one effector were mated to an array of ~330 effectors in groups of ~10 queries at a time ("Analysis Set"). The arrays were then imaged using a high-resolution camera and the spot sizes were quantified using SGAtools (http://sgatools.ccbr.utoronto.ca/). Outlier spot sizes flagged by the Jackknife filter (JK) in SGAtools were removed and the average and standard deviation of the remaining values were calculated and normalized to the average empty vector control. This .zip archive includes spreadsheets that encompass the raw SGAtools data output from the paper for analysis sets 1-10.UrbanusMSB_SGA.zipUrbanus_SGA_1-10.zipSGA output for analysis sets 11-20.Query strains that express one effector were mated to an array of ~330 effectors in groups of ~10 queries at a time ("Analysis Set"). The arrays were then imaged using a high-resolution camera and the spot sizes were quantified using SGAtools (http://sgatools.ccbr.utoronto.ca/). Outlier spot sizes flagged by the Jackknife filter (JK) in SGAtools were removed and the average and standard deviation of the remaining values were calculated and normalized to the average empty vector control. This .zip archive includes spreadsheets that encompass the raw SGAtools data output from the paper for analysis sets 11-20.Urbanus_SGA_11-20.zipSGA output for analysis sets 21-30.Query strains that express one effector were mated to an array of ~330 effectors in groups of ~10 queries at a time ("Analysis Set"). The arrays were then imaged using a high-resolution camera and the spot sizes were quantified using SGAtools (http://sgatools.ccbr.utoronto.ca/). Outlier spot sizes flagged by the Jackknife filter (JK) in SGAtools were removed and the average and standard deviation of the remaining values were calculated and normalized to the average empty vector control. This .zip archive includes spreadsheets that encompass the raw SGAtools data output from the paper for analysis sets 21-30.Urbanus_SGA_21-30.zipSGA output for analysis sets 31-37.Query strains that express one effector were mated to an array of ~330 effectors in groups of ~10 queries at a time ("Analysis Set"). The arrays were then imaged using a high-resolution camera and the spot sizes were quantified using SGAtools (http://sgatools.ccbr.utoronto.ca/). Outlier spot sizes flagged by the Jackknife filter (JK) in SGAtools were removed and the average and standard deviation of the remaining values were calculated and normalized to the average empty vector control. This .zip archive includes spreadsheets that encompass the raw SGAtools data output from the paper for analysis sets 31-37.Urbanus_SGA_31-37.zip Pathogens deliver complex arsenals of translocated effector proteins to host cells during infection, but the extent to which these proteins are regulated once inside the eukaryotic cell remains poorly defined. Among all bacterial pathogens, Legionella pneumophila maintains the largest known set of translocated substrates, delivering over 300 proteins to the host cell via its Type IVB, Icm/Dot translocation system. Backed by a few notable examples of effector–effector regulation in L. pneumophila, we sought to define the extent of this phenomenon through a systematic analysis of effector–effector functional interaction. We used Saccharomyces cerevisiae, an established proxy for the eukaryotic host, to query > 108,000 pairwise genetic interactions between two compatible expression libraries of ~330 L. pneumophila‐translocated substrates. While capturing all known examples of effector–effector suppression, we identify fourteen novel translocated substrates that suppress the activity of other bacterial effectors and one pair with synergistic activities. In at least nine instances, this regulation is direct—a hallmark of an emerging class of proteins called metaeffectors, or “effectors of effectors”. Through detailed structural and functional analysis, we show that metaeffector activity derives from a diverse range of mechanisms, shapes evolution, and can be used to reveal important aspects of each cognate effector's function. Metaeffectors, along with other, indirect, forms of effector–effector modulation, may be a common feature of many intracellular pathogens—with unrealized potential to inform our understanding of how pathogens regulate their interactions with the host cell.

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

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.