Phosphene Perception Relates to Visual Cortex Glutamate Levels and Covaries with Atypical Visuospatial Awareness

Phosphenes are illusory visual percepts produced by the application of transcranial magnetic stimulation to occipital cortex. Phosphene thresholds, the minimum stimulation intensity required to reliably produce phosphenes, are widely used as an index of cortical excitability. However, the neural basis of phosphene thresholds and their relationship to individual differences in visual cognition are poorly understood. Here, we investigated the neurochemical basis of phosphene perception by measuring basal GABA and glutamate levels in primary visual cortex using magnetic resonance spectroscopy. We further examined whether phosphene thresholds would relate to the visuospatial phenomenology of grapheme-color synesthesia, a condition characterized by atypical binding and involuntary color photisms. Phosphene thresholds negatively correlated with glutamate concentrations in visual cortex, with lower thresholds associated with elevated glutamate. This relationship was robust, present in both controls and synesthetes, and exhibited neurochemical, topographic, and threshold specificity. Projector synesthetes, who experience color photisms as spatially colocalized with inducing graphemes, displayed lower phosphene thresholds than associator synesthetes, who experience photisms as internal images, with both exhibiting lower thresholds than controls. These results suggest that phosphene perception is driven by interindividual variation in glutamatergic activity in primary visual cortex and relates to cortical processes underlying individual differences in visuospatial awareness

Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology.

Idiopathic scoliosis (IS) is a structural lateral spinal curvature of ≥10° that affects up to 3% of otherwise healthy children and can lead to life-long problems in severe cases. It is well-established that IS is a genetic disorder. Previous studies have identified genes that may contribute to the IS phenotype, but the overall genetic etiology of IS is not well understood. We used exome sequencing to study five multigenerational families with IS. Bioinformatic analyses identified unique and low frequency variants (minor allele frequency ≤5%) that were present in all sequenced members of the family. Across the five families, we identified a total of 270 variants with predicted functional consequences in 246 genes, and found that eight genes were shared by two families. We performed GO term enrichment analyses, with the hypothesis that certain functional annotations or pathways would be enriched in the 246 genes identified in our IS families. Using three complementary programs to complete these analyses, we identified enriched categories that include stereocilia and other actin-based cellular projections, cilia and other microtubule-based cellular projections, and the extracellular matrix (ECM). Our results suggest that there are multiple paths to IS and provide a foundation for future studies of IS pathogenesis

Altered neural dynamics in people who report spontaneous out of body experiences

It has been suggested that individual differences in cortical excitability leading to disruption of the timing and integration of sensory information processing may explain why some people have out of body experiences (OBE) in the absence of any known pathological or psychiatric condition. Here we recorded EEG from people who either had, or had not experienced an OBE in order to investigate the neural dynamics of OBE in the non-clinical population. A screening questionnaire was completed by 551 people, 24% of whom reported having at least one OBE. Participants who were free of any psychiatric or neurological diagnoses, including migraines, were invited to take part in subsequent EEG recording. EEG data were obtained from 19 people who had had an OBE and 20 who had not. Amplitude of the visual P1 ERP deflection and consistency of alpha-band phase locking were significantly reduced in the participants who had had an OBE. We did not find any group differences in resting state power or in visually induced gamma oscillations. These results provide support for the claim that cortical differences, particularly with respect to the timing of visual information processing, may give rise to OBE in clinically healthy individuals. To our knowledge, this study is the first to compare EEG variables obtained from people who have, and have not, had an OBE

The role of networks to overcome large-scale challenges in tomography : the non-clinical tomography users research network

Our ability to visualize and quantify the internal structures of objects via computed tomography (CT) has fundamentally transformed science. As tomographic tools have become more broadly accessible, researchers across diverse disciplines have embraced the ability to investigate the 3D structure-function relationships of an enormous array of items. Whether studying organismal biology, animal models for human health, iterative manufacturing techniques, experimental medical devices, engineering structures, geological and planetary samples, prehistoric artifacts, or fossilized organisms, computed tomography has led to extensive methodological and basic sciences advances and is now a core element in science, technology, engineering, and mathematics (STEM) research and outreach toolkits. Tomorrow's scientific progress is built upon today's innovations. In our data-rich world, this requires access not only to publications but also to supporting data. Reliance on proprietary technologies, combined with the varied objectives of diverse research groups, has resulted in a fragmented tomography-imaging landscape, one that is functional at the individual lab level yet lacks the standardization needed to support efficient and equitable exchange and reuse of data. Developing standards and pipelines for the creation of new and future data, which can also be applied to existing datasets is a challenge that becomes increasingly difficult as the amount and diversity of legacy data grows. Global networks of CT users have proved an effective approach to addressing this kind of multifaceted challenge across a range of fields. Here we describe ongoing efforts to address barriers to recently proposed FAIR (Findability, Accessibility, Interoperability, Reuse) and open science principles by assembling interested parties from research and education communities, industry, publishers, and data repositories to approach these issues jointly in a focused, efficient, and practical way. By outlining the benefits of networks, generally, and drawing on examples from efforts by the Non-Clinical Tomography Users Research Network (NoCTURN), specifically, we illustrate how standardization of data and metadata for reuse can foster interdisciplinary collaborations and create new opportunities for future-looking, large-scale data initiatives

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Abstract 4079: Reversal of immune evasion mediated by HER2 requires both humoral and cellular HER-2 targeted immune interventions

Abstract Objectives: HER2 over-expression in breast cancer is associated with a poor prognosis and HER2 is an intense target of immunotherapy with both humoral and T cell -base approaches. HER2 expression is also known to facilitate the escape of tumor cells from immune surveillance by down-regulating MHC class I, resulting in a reduced sensitivity to CTL lysis. Restoring tumor cell MHC Class I expression and reversing their immune evasion are therefore important strategies in the design of immunotherapy against HER2 expressing tumors. In this study we investigated the effects of monoclonal antibody trastuzumab and T help-1 associated cytokines IFN-γ and TNF-A on HLA Class I expression and the susceptibilities to CTL lysis of human HER2 expressing tumor cell lines. Methods: Breast cancer cell lines MCF7, SKBR3, BT474 and ovarian cancer cell line SKOV3 were treated with trastuzumab only, combination of IFN-γ and TNF-A or trastuzumab with IFN-γ and TNF-A. Cell surface expressions of HLA ABC were examined by flow cytometric analysis. The susceptibility of tumor cells to HER2 specific CD8+ T cell recognition and CTL lysis were assessed by measurement of CD8+ T cell IFN-γ secretion and flow cytometric analysis respectively. Results: Th1 cytokines IFN-γ and TNF-A dramatically increased HLA ABC expressions on all tumor lines compared to untreated cells, [ MCF7 (p=0.04); SKBR3 (p=0.02); SCOV3 (p=0.02) and BT474 (p=0.04)], while trastuzumab alone showed little impact on HLA ABC up-regulation. When treated with a combination of trastuzumab, IFN-γ and TNF-A tumor cells displayed synergistically enhanced HLA ABC expression [MCF7 (p=0.02); SKBR3 (p=0.004); SKOV3 (0.006) and BT474 (p=0.03)]. We observed that IFN-γ and TNF-A treatment was able to remarkably increase CD8+ T cell recognition and CTL lysis of low and intermediate HER2 expressing tumors [ MCF7(p=0.03) and SKOV3(0.02)], but not High HER2 tumor[ SKBR3(p=0.07)]. Only a combined treatment of trastuzumab, IFN-γ and TNF-A rendered SKBR3 susceptible to a significant killing by CTL (p=0.02). To investigate the impact of other HER family members EGFR and HER3 on MHC class I expression , HER2 over-expressing breast cancer cell lines BT474 and SKBR3 were pre-treated with EGF or Heregulin, then subjected to IFN-γ and TNF-A treatments. Activation of HER1 and HER3 signaling made HER2 over-expressing cells resistant to the effect of MHC class I up-regulation by IFN-γ and TNF-A. Conclusion: Both humoral and cellular immune HER-2 targeted interventions are required to reverse immune escape mediated by HER2; in addition to targeting HER2, targeting HER1 and HER3 signaling elements should also be included in order to abrogate the cross talk between HER family members and more effectively inhibit the HER2 signaling pathway. Citation Format: Shuwen Xu, Jessica Cintolo, Jashodeep Datta, Cinthia Rosemblit, Erik Berk, Julia Terhune, Elizabeth Fitzpatrick, Brian Czerniecki. Reversal of immune evasion mediated by HER2 requires both humoral and cellular HER-2 targeted immune interventions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4079. doi:10.1158/1538-7445.AM2014-407

Severity of idiopathic scoliosis is associated with differential methylation : An epigenome‐wide association study of monozygotic twins with idiopathic scoliosis

Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference >10°) and 2 concordant (Cobb angle difference ≤2°). Genome‐wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR < 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper‐ or hypo‐methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS

Definitions, terminology, and related concepts of “racial health equity”: a scoping review protocol

Abstract Background In the USA, access to quality healthcare varies greatly across racial and ethnic groups, resulting in significant health disparities. A new term, “racial health equity” (RHE), is increasingly reported in the medical literature, but there is currently no consensus definition of the term. Additionally, related terms such as “health disparities,” “health inequities,” and “equality” have been inconsistently used when defining RHE. Methods The primary purpose of this scoping review is to investigate the current use and underlying concepts used to define racial health equity. The study will address two key questions: (1) “What terminology and definitions have been used to characterize RHE?” and (2) “What knowledge gaps and challenges are present in the current state of RHE research and theory?” The review will collect and analyze data from three sources: (1) websites from key national and international health organizations, (2) theoretical and narrative published articles, and (3) evidence synthesis studies addressing interventions targeting racial health equity and minority stakeholder engagement. Discussion Defining “racial health equity” and related terminology is the first step to advancing racial health equity within the USA. This review aims to offer an improved understanding of RHE constructs and definitions, bringing greater unity to national racial health equity research efforts across disciplines. Systematic review registration This protocol is registered with the Open Science Framework at https://osf.io/7pvzq

Supplemental Material for Baschal et al., 2018

<p>Idiopathic scoliosis (IS) is a complex genetic disease of unknown etiology. We completed exome sequencing for five IS families and performed GO term enrichment analyses on the resulting variant lists. Overall, we identified enriched categories in our affected families that include stereocilia and other actin-based cellular projections, cilia and other microtubule-based cellular projections, and the extracellular matrix (ECM). Our results suggest that there are multiple paths to IS and provide a foundation for future studies of IS pathogenesis.</p><p></p