Graphical Perception of Continuous Quantitative Maps: the Effects of Spatial Frequency and Colormap Design

Continuous 'pseudocolor' maps visualize how a quantitative attribute varies smoothly over space. These maps are widely used by experts and lay citizens alike for communicating scientific and geographical data. A critical challenge for designers of these maps is selecting a color scheme that is both effective and aesthetically pleasing. Although there exist empirically grounded guidelines for color choice in segmented maps (e.g., choropleths), continuous maps are significantly understudied, and their color-coding guidelines are largely based on expert opinion and design heuristics--many of these guidelines have yet to be verified experimentally. We conducted a series of crowdsourced experiments to investigate how the perception of continuous maps is affected by colormap characteristics and spatial frequency (a measure of data complexity). We find that spatial frequency significantly impacts the effectiveness of color encodes, but the precise effect is task-dependent. While rainbow schemes afforded the highest accuracy in quantity estimation irrespective of spatial complexity, divergent colormaps significantly outperformed other schemes in tasks requiring the perception of high-frequency patterns. We interpret these results in relation to current practices and devise new and more granular guidelines for color mapping in continuous maps

A Phase I Study of Ad5-GUCY2C-PADRE in Stage I and II Colon Cancer Patients

Background Ad5-GUCY2C-PADRE is a replication-deficient human type 5 recombinant adenovirus (Ad5) vaccine encoding guanylyl cyclase C (GUCY2C) fused to the PAn DR Epitope (PADRE). GUCY2C, a paracrine hormone receptor producing the second messenger cyclic GMP (cGMP), is selectively expressed by intestinal epithelial cells and a subset of hypothalamic neurons, but not other tissues. Importantly, GUCY2C is over-expressed in nearly all primary and metastatic human colorectal tumors. Preclinical studies in mice demonstrated selective tolerance of GUCY2C-specific CD4+ T cells, but not CD8+ T or B cells, necessitating inclusion of the exogenous CD4+ T helper cell epitope PADRE to maximize GUCY2C-specific CD8+ T-cell and antibody responses and antitumor efficacy, without autoimmunity. Patients and Methods This is an open-label, single arm “proof-of-concept” study evaluating a single dose level of Ad5-GUCY2C-PADRE as a vaccine for surgically-treated, node-negative colon cancer subjects (NCT01972737). Patients received a single intramuscular administration of 1011 Ad5-GUCY2C-PADRE viral particles. Safety and immunomonitoring were examined at 30, 90 and 180 days following vaccination. Primary objectives were to determine the safety, tolerability, and toxicity of Ad5-GUCY2C-PADRE and to determine whether Ad5- GUCY2C-PADRE induces GUCY2C-specific immune responses. The study employed a joint efficacy-toxicity design and included stopping rules for either efficacy or toxicity.Results here were obtained during the planned interim analysis following accrual of 10 subjects. Results The vaccine was well tolerated, producing only mild adverse events (AEs). Short-lived injection site pain/swelling, body aches, and chills were the most commonly observed AEs and occurred in 30-40% of subjects. GUCY2C-specific antibody and T-cell responses were observed in a subset of subjects. Consistent with preclinical mouse data, T-cell responses were composed of CD8+, but not CD4+, T cells. Importantly, GUCY2C-specific responses occurred only in subjects with low Ad5 neutralizing antibody (NAb) titers at the time of vaccination, suggesting that pre-existing Ad5 immunity limits Ad5-GUCY2C-PADRE immunogenicity. Conclusions Interim analysis of 10 subjects receiving Ad5-GUCY2C-PADRE demonstrates proof-of-concept that GUCY2C is immunogenic in humans and that GUCY2C-directed vaccination is safe. Moreover, the presence of GUCY2C-specific antibody and CD8+ T-cell, but not CD4+ T-cell, responses is consistent with selective CD4+ T-cell tolerance observed in mouse models. These data establish GUCY2C as a safe and immunogenic target for immunotherapy in cancer patients. Poster presented at: Immunotherapy of Cancer (SITC) 30th Annual Meeting in National Harbor Maryland.https://jdc.jefferson.edu/petposters/1001/thumbnail.jp

BMP-2/6 Heterodimer Is More Effective than BMP-2 or BMP-6 Homodimers as Inductor of Differentiation of Human Embryonic Stem Cells

Bone Morphogenetic Protein (BMP) signaling pathways are involved in differentiation of stem cells into diverse cell types, and thus BMPs can be used as main guidance molecules for in vitro differentiation of human stem cells.We have analyzed the ability for inducing differentiation of the heterodimer BMP-2/BMP-6 (BMP-2/6) compared to the homodimers BMP-2 or BMP-6, using human embryonic stem (hES) cells H9 as model system. When incubated in a medium with high concentration of basic fibroblastic growth factor (FGF2), 100 ng/ml of human recombinant BMPs induced morphological changes and differentiation of hES cells in 24 to 48 hours. After 5 days, expression of differentiation markers was induced and quantified by quantitative PCR (qPCR) and flow cytometry. BMP-2/6 exhibited stronger activity for the induction of the expression of trophectodermal (CDX2) and endodermal (SOX17, GATA4, AFP) markers than BMP-2 or BMP-6 homodimers. BMP-2/6 also induced the expression of BMPR2 gene more effectively than BMP-2 or BMP-6 when used at the same concentration and time. Moreover, the percentage of cells expressing the surface endodermal marker CXCR4 was also increased for the heterodimer when compared to both homodimers. BMP-2/6 was a more potent activator of Smad-dependent (SMAD1/5) and Smad-independent signaling (mitogen-activated protein kinases ERK and p38) than BMP-2 and BMP-6, and the activation of these pathways might play a role in its increased potency for inducing hES cell differentiation.Therefore, we conclude that BMP-2/6 is more potent than BMP-2 or BMP-6 for inducing differentiation of hES cells, and it can be used as a more powerful substitute of these BMPs in in vitro differentiation guidance

Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD

BACKGROUND: A new locus for amyotrophic lateral sclerosis – frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p. METHODS: We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2) and undertook mutational screening of candidate genes within this locus. RESULTS: Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X) in the intraflagellar transport 74 (IFT74) gene in family 476 (F476), but no mutation was detected within IFT74 in family 2 (F2). While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids) led us to sequence the open reading frame of this gene in a large number of ALS and FTD cases (n = 420). An additional sequence variant (G58D) was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples. CONCLUSION: Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson’s disease, and Alzheimer’s disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected by clinical teams after clinical examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also in only participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14–2·70; p=1·05 × 10–⁴⁸), SNCA (rs7681440; OR 0·73, 0·66–0·81; p=6·39 × 10–¹⁰), and GBA (rs35749011; OR 2·55, 1·88–3·46; p=1·78 × 10–⁹). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27–1·79; p=2·21 × 10–⁶); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease

Highlights From the Annual Meeting of the American Epilepsy Society 2022

With more than 6000 attendees between in-person and virtual offerings, the American Epilepsy Society Meeting 2022 in Nashville, felt as busy as in prepandemic times. An ever-growing number of physicians, scientists, and allied health professionals gathered to learn a variety of topics about epilepsy. The program was carefully tailored to meet the needs of professionals with different interests and career stages. This article summarizes the different symposia presented at the meeting. Basic science lectures addressed the primary elements of seizure generation and pathophysiology of epilepsy in different disease states. Scientists congregated to learn about anti-seizure medications, mechanisms of action, and new tools to treat epilepsy including surgery and neurostimulation. Some symposia were also dedicated to discuss epilepsy comorbidities and practical issues regarding epilepsy care. An increasing number of patient advocates discussing their stories were intertwined within scientific activities. Many smaller group sessions targeted more specific topics to encourage member participation, including Special Interest Groups, Investigator, and Skills Workshops. Special lectures included the renown Hoyer and Lombroso, an ILAE/IBE joint session, a spotlight on the impact of Dobbs v. Jackson on reproductive health in epilepsy, and a joint session with the NAEC on coding and reimbursement policies. The hot topics symposium was focused on traumatic brain injury and post-traumatic epilepsy. A balanced collaboration with the industry allowed presentations of the latest pharmaceutical and engineering advances in satellite symposia

A comprehensive screening of copy number variability in dementia with Lewy bodies

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk. (C) 2019 Elsevier Inc. All rights reserved.Peer reviewe

Frontotemporal dementia and its subtypes: a genome-wide association study

SummaryBackground Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with {FTD} and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with {FTD} and 4308 controls), we did separate association analyses for each {FTD} subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and {FTD} overlapping with motor neuron disease FTD-MND), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, \{HLA\} locus (immune system), for rs9268877 (p=1·05 × 10−8; odds ratio=1·204 95% \{CI\} 1·11–1·30), rs9268856 (p=5·51 × 10−9; 0·809 0·76–0·86) and rs1980493 (p value=1·57 × 10−8, 0·775 0·69–0·86) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural \{FTD\} subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10−7; 0·814 0·71–0·92). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders