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The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Background: Health inequalities disproportionally affect indigenous people in Guatemala. Previous studies have noted that the disadvantageous situation of indigenous people is the result of complex and structural elements such as social exclusion, racism and discrimination. These elements need to be addressed in order to tackle the social determinants of health. This research was part of a larger participatory collaboration between Centro de Estudios para la Equidad y Gobernanza en los Servicios de Salud (CEGSS) and community based organizations aiming to implement social accountability in rural indigenous municipalities of Guatemala. Discrimination while seeking health care services in public facilities was ranked among the top three problems by communities and that should be addressed in the social accountability intervention. This study aimed to understand and categorize the episodes of discrimination as reported by indigenous communities.Methods: A participatory approach was used, involving CEGSS’s researchers and field staff and community leaders. One focus group in one rural village of 13 different municipalities was implemented. Focus groups were aimed at identifying instances of mistreatment in health care services and documenting the account of those who were affected or who witnessed them. All of the 132 obtained episodes were transcribed and scrutinized using a thematic analysis.Results: Episodes described by participants ranged from indifference to violence (psychological, symbolic, and physical), including coercion, mockery, deception and racism. Different expressions of discrimination and mistreatment associated to poverty, language barriers, gender, ethnicity and social class were narrated by participants.Conclusions: Addressing mistreatment in public health settings will involve tackling the prevalent forms of discrimination, including racism. This will likely require profound, complex and sustained interventions at the programmatic and policy levels beyond the strict realm of public health services. Future studies should assess the magnitude of the occurrence of episodes of maltreatment and racism within indigenous areas and also explore the providers’ perceptions about the problem.

AbstractLeptin influences eating behavior. Exposure to early adversity is associated with eating behaviour disorders and metabolic syndrome, but the role of the leptin receptor on this relationship is poorly explored. We investigated whether individual differences in brain region specific leptin receptor (LepR) gene networks could moderate the effects of early adversity on eating behavior and metabolism. We created an expression-based polygenic risk score (ePRS) reflecting variations in the function of LepR gene network in prefrontal cortex and hypothalamus to investigate the interactions between a cumulative index of postnatal adversity on eating behavior in two independent birth cohorts (MAVAN and GUSTO). To explore whether variations in the prefrontal cortex or hypothalamic genetic scores could be associated with metabolic measurements, we also assessed the relationship between LepR-ePRS and fasting blood glucose and leptin levels in a third independent cohort (ALSPAC). We identified significant interaction effects between postnatal adversity and prefrontal-based LepR-ePRS on the Child Eating Behavior Questionnaire scores. In MAVAN, we observed a significant interaction effect on food enjoyment at 48 months (β = 61.58, p = 0.015) and 72 months (β = 97.78, p = 0.001); food responsiveness at 48 months (β = 83.79, p = 0.009) satiety at 48 months (β = −43.63, p = 0.047). Similar results were observed in the GUSTO cohort, with a significant interaction effect on food enjoyment (β = 30.48, p = 0.006) food fussiness score (β = −24.07, p = 0.02) and satiety score at 60 months (β = −17.00, p = 0.037). No effects were found when focusing on the hypothalamus-based LepR-ePRS on eating behavior in MAVAN and GUSTO cohorts, and there was no effect of hypothalamus and prefrontal cortex based ePRSs on metabolic measures in ALSPAC. Our study indicated that exposure to postnatal adversity interacts with prefrontal cortex LepR-ePRS to moderate eating behavior, suggesting a neurobiological mechanism associated with the development of eating behavior problems in response to early adversity. The knowledge of these mechanisms may guide the understanding of eating patterns associated with risk for obesity in response to fluctuations in stress exposure early in life.

Background: In our previous investigations of the role of the extracellular matrix (ECM) in promoting neurite growth we have observed that a permissive laminin (LN) substrate stimulates differential growth responses in subpopulations of mature dorsal root ganglion (DRG) neurons. DRG neurons expressing Trk and p75 receptors grow neurites on a LN substrate in the absence of neurotrophins, while isolectin B4-binding neurons (IB4+) do not display significant growth under the same conditions. We set out to determine whether there was an expression signature of the LN-induced neurite growth phenotype. Using a lectin binding protocol IB4+ neurons were isolated from dissociated DRG neurons, creating two groups - IB4+ and IB4-. A small-scale microarray approach was employed to screen the expression of a panel of ECM-associated genes following dissociation (t=0) and after 24 hr culture on LN (t=24LN). This was followed by qRT-PCR and immunocytochemistry of selected genes. Results: The microarray screen showed that 36 of the 144 genes on the arrays were consistently expressed by the neurons. The array analyses showed that six genes had lower expression in the IB4+ neurons compared to the IB4- cells at t=0 (CTSH, Icam1, Itgβ1, Lamb1, Plat, Spp1), and one gene was expressed at higher levels in the IB4+ cells (Plaur). qRT-PCR was carried out as an independent assessment of the array results. There were discrepancies between the two methods, with qRT-PCR confirming the differences in Lamb1, Plat and Plaur, and showing decreased expression of AdamTs1, FN, and Icam in the IB4+ cells at t=0. After 24 hr culture on LN, there were no significant differences detected by qRT-PCR between the IB4+ and IB4- cells. However, both groups showed upregulation of Itgβ1 and Plaur after 24 hr on LN, the IB4+ group also had increased Plat, and the IB4- cells showed decreased Lamb1, Icam1 and AdamTs1. Further, the array screen also detected a number of genes (not subjected to qRT-PCR) expressed similarly by both populations in relatively high levels but not detectably influenced by time in culture (Bsg, Cst3, Ctsb, Ctsd, Ctsl, Mmp14, Mmp19, Sparc. We carried out immunohistochemistry to confirm expression of proteins encoded by a number of these genes. Conclusions:Our results show that 1B4+ and IB4- neurons differ in the expression of several genes that are associated with responsiveness to the ECM prior to culturing (AdamTs1, FN, Icam1, Lamb1, Plat, Plaur). The data suggest that the genes expressed at higher levels in the IB4- neurons could contribute to the initial growth response of these cells in a permissive environment and could also represent a common injury response that subsequently promotes axon regeneration. The differential expression of several extracellular matrix molecules (FN, Lamb1, Icam) may suggest that the IB4- neurons are capable of maintaining /secreting their local extracellular environment which could aid in the regenerative process. Overall, these data provide new information on potential targets that could be manipulated to enhance axonal regeneration in the mature nervous system.

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

Background: Clinical trials that end prematurely (or “terminate”) raise financial, ethical, and scientific concerns. The extent to which the results of such trials are disseminated and the reasons for termination have not been well characterized. Methods and Findings: A cross-sectional, descriptive study of terminated clinical trials posted on the ClinicalTrials.gov results database as of February 2013 was conducted. The main outcomes were to characterize the availability of primary outcome data on ClinicalTrials.gov and in the published literature and to identify the reasons for trial termination. Approximately 12% of trials with results posted on the ClinicalTrials.gov results database (905/7,646) were terminated. Most trials were terminated for reasons other than accumulated data from the trial (68%; 619/905), with an insufficient rate of accrual being the lead reason for termination among these trials (57%; 350/619). Of the remaining trials, 21% (193/905) were terminated based on data from the trial (findings of efficacy or toxicity) and 10% (93/905) did not specify a reason. Overall, data for a primary outcome measure were available on ClinicalTrials.gov and in the published literature for 72% (648/905) and 22% (198/905) of trials, respectively. Primary outcome data were reported on the ClinicalTrials.gov results database and in the published literature more frequently (91% and 46%, respectively) when the decision to terminate was based on data from the trial. Conclusions: Trials terminate for a variety of reasons, not all of which reflect failures in the process or an inability to achieve the intended goals. Primary outcome data were reported most often when termination was based on data from the trial. Further research is needed to identify best practices for disseminating the experience and data resulting from terminated trials in order to help ensure maximal societal benefit from the investments of trial participants and others involved with the study. DATA_Terminated Trials in ClinicalTrialsgov Results Database (19 Feb 2013)CSV data file containing data retrieved from the ClinicalTrials.gov registry and results database on February 19, 2013. Additional details are available in the ReadMe file.

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

Assemblies of vertically connected neurons in the cerebral cortex form information processing units (columns) that participate in the distribution and segregation of sensory signals. Despite well-accepted models of columnar architecture, functional mechanisms of inter-laminar communication remain poorly understood. Hence, the purpose of the present investigation was to examine the effects of sensory information features on columnar response properties. Using acute recording techniques, extracellular response activity was collected from the right hemisphere of eight mature cats (felis catus). Recordings were conducted with multichannel electrodes that permitted the simultaneous acquisition of neuronal activity within primary auditory cortex columns. Neuronal responses to simple (pure tones), complex (noise burst and frequency modulated sweeps), and ecologically relevant (con-specific vocalizations) acoustic signals were measured. Collectively, the present investigation demonstrates that despite consistencies in neuronal tuning (characteristic frequency), irregularities in discharge activity between neurons of individual A1 columns increase as a function of spectral (signal complexity) and temporal (duration) acoustic variations. Multi-unit responses to acoustic signals within A1 columnsThe data set consists of eight multi-unit electrophysiology experiments located within a single .zip file. Acoustic feature (signal type and duration) are in subfolders where data rasters for each recording session conducted can be found. Columns represent time and rows trial number. Data is presented as Matlab files.DRYAD.zip

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

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