Genetic and Neuroanatomical Support for Functional Brain Network Dynamics in Epilepsy

Focal epilepsy is a devastating neurological disorder that affects an overwhelming number of patients worldwide, many of whom prove resistant to medication. The efficacy of current innovative technologies for the treatment of these patients has been stalled by the lack of accurate and effective methods to fuse multimodal neuroimaging data to map anatomical targets driving seizure dynamics. Here we propose a parsimonious model that explains how large-scale anatomical networks and shared genetic constraints shape inter-regional communication in focal epilepsy. In extensive ECoG recordings acquired from a group of patients with medically refractory focal-onset epilepsy, we find that ictal and preictal functional brain network dynamics can be accurately predicted from features of brain anatomy and geometry, patterns of white matter connectivity, and constraints complicit in patterns of gene coexpression, all of which are conserved across healthy adult populations. Moreover, we uncover evidence that markers of non-conserved architecture, potentially driven by idiosyncratic pathology of single subjects, are most prevalent in high frequency ictal dynamics and low frequency preictal dynamics. Finally, we find that ictal dynamics are better predicted by white matter features and more poorly predicted by geometry and genetic constraints than preictal dynamics, suggesting that the functional brain network dynamics manifest in seizures rely on - and may directly propagate along - underlying white matter structure that is largely conserved across humans. Broadly, our work offers insights into the generic architectural principles of the human brain that impact seizure dynamics, and could be extended to further our understanding, models, and predictions of subject-level pathology and response to intervention

Rapamycin Conditioning of Dendritic Cells Differentiated from Human ES Cells Promotes a Tolerogenic Phenotype

While human embryonic stem cells (hESCs) may one day facilitate the treatment of degenerative diseases requiring cell replacement therapy, the success of regenerative medicine is predicated on overcoming the rejection of replacement tissues. Given the role played by dendritic cells (DCs) in the establishment of immunological tolerance, we have proposed that DC, rendered tolerogenic during their differentiation from hESC, might predispose recipients to accept replacement tissues. As a first step towards this goal, we demonstrate that DC differentiated from H1 hESCs (H1-DCs) are particularly responsive to the immunosuppressive agent rapamycin compared to monocyte-derived DC (moDC). While rapamycin had only modest impact on the phenotype and function of moDC, H1-DC failed to upregulate CD40 upon maturation and displayed reduced immunostimulatory capacity. Furthermore, coculture of naïve allogeneic T cells with rapamycin-treated H1-DC promoted an increased appearance of CD25hi Foxp3+ regulatory T cells, compared to moDC. Our findings suggest that conditioning of hESC-derived DC with rapamycin favours a tolerogenic phenotype

Physical Characterization of the December 2017 Outburst of the Centaur 174P/Echeclus

The Centaurs are the small solar system bodies intermediate between the active inner solar system Jupiter Family Comets and their inactive progenitors in the trans-Neptunian region. Among the fraction of Centaurs which show comet-like activity, 174P/Echeclus is best known for its massive 2005 outburst in which a large apparently active fragment was ejected above the escape velocity from the primary nucleus. We present visible imaging and near-infrared spectroscopy of Echeclus during the first week after its December 2017 outburst taken at the Faulkes North & South Telescopes and the NASA IRTF, the largest outburst since 2005. The coma was seen to be highly asymmetric. A secondary peak was seen in the near-infrared 2D spectra, which is strongly hinted at in the visible images, moving hyperbolically with respect to the nucleus. The retrieved reflectance spectrum of Echelcus is consistent with the unobscured nucleus but becomes bluer when a wider extraction aperture is used. We find that Echeclus's coma is best explained as dominated by large blue dust grains, which agrees with previous work. We also conducted a high-resolution orbital integration of Echeclus's recent evolution and found no large orbital changes that could drive its modern evolution. We interpret the second peak in the visible and near-infrared datasets as a large cloud of larger-than-dust debris ejected at the time of outburst. If Echeclus is typical of the Centaurs, there may be several debris ejection or fragmentation events per year on other Centaurs that are going unnoticed.Comment: Accepted for publication in the Astronomical Journal, 18 pages, 4 figures, 4 table

SynapseJ: An Automated, Synapse Identification Macro for ImageJ

While electron microscopy represents the gold standard for detection of synapses, a number of limitations prevent its broad applicability. A key method for detecting synapses is immunostaining for markers of pre- and post-synaptic proteins, which can infer a synapse based upon the apposition of the two markers. While immunostaining and imaging techniques have improved to allow for identification of synapses in tissue, analysis and identification of these appositions are not facile, and there has been a lack of tools to accurately identify these appositions. Here, we delineate a macro that uses open-source and freely available ImageJ or FIJI for analysis of multichannel, z-stack confocal images. With use of a high magnification with a high NA objective, we outline two methods to identify puncta in either sparsely or densely labeled images. Puncta from each channel are used to eliminate non-apposed puncta and are subsequently linked with their cognate from the other channel. These methods are applied to analysis of a pre-synaptic marker, bassoon, with two different post-synaptic markers, gephyrin and N-methyl-d-aspartate (NMDA) receptor subunit 1 (NR1). Using gephyrin as an inhibitory, post-synaptic scaffolding protein, we identify inhibitory synapses in basolateral amygdala, central amygdala, arcuate and the ventromedial hypothalamus. Systematic variation of the settings identify the parameters most critical for this analysis. Identification of specifically overlapping puncta allows for correlation of morphometry data between each channel. Finally, we extend the analysis to only examine puncta overlapping with a cytoplasmic marker of specific cell types, a distinct advantage beyond electron microscopy. Bassoon puncta are restricted to virally transduced, pedunculopontine tegmental nucleus (PPN) axons expressing yellow fluorescent protein. NR1 puncta are restricted to tyrosine hydroxylase labeled dopaminergic neurons of the substantia nigra pars compacta (SNc). The macro identifies bassoon-NR1 overlap throughout the image, or those only restricted to the PPN-SNc connections. Thus, we have extended the available analysis tools that can be used to study synapses in situ. Our analysis code is freely available and open-source allowing for further innovation

NewsClaims: A New Benchmark for Claim Detection from News with Attribute Knowledge

Claim detection and verification are crucial for news understanding and have emerged as promising technologies for mitigating news misinformation. However, most existing work has focused on claim sentence analysis while overlooking crucial background attributes (e.g., claimer, claim objects). In this work, we present NewsClaims, a new benchmark for knowledge-aware claim detection in the news domain. We redefine the claim detection problem to include extraction of additional background attributes related to each claim and release 889 claims annotated over 143 news articles. NewsClaims aims to benchmark claim detection systems in emerging scenarios, comprising unseen topics with little or no training data. To this end, we provide a comprehensive evaluation of zero-shot and prompt-based baselines for NewsClaims.Comment: Preprin

Test site predicts HIV care linkage and antiretroviral therapy initiation: a prospective 3.5 year cohort study of HIV-positive testers in northern Tanzania

Abstract Background Linkage to HIV care is crucial to the success of antiretroviral therapy (ART) programs worldwide, loss to follow up at all stages of the care continuum is frequent, and long-term prospective studies of care linkage are currently lacking. Methods Consecutive clients who tested HIV-positive were enrolled from four HIV testing centers (1 health facility and 3 community-based centers) in the Kilimanjaro region of Tanzania as part of the larger Coping with HIV/AIDS in Tanzania (CHAT) prospective observational study. Biannual interviews were conducted over 3.5 years, assessing care linkage, retention, and mental health. Bivariable and multivariate logistic regression analyses were conducted to determine associations with early death (prior to the second follow up interview) and delayed (>6 months post-test) or failed care linkage. Results A total of 263 participants were enrolled between November, 2008 and August, 2009 and 240 participants not already linked to care were retained in the final dataset. By 6 months after enrollment, 169 (70.4 %) of 240 participants had presented to an HIV care and treatment facility; 41 (17.1 %) delayed more than 6 months, 15 (6.3 %) died, and 15 (6.3 %) were lost to follow up. Twenty-six patients died before their second follow up visit and were analyzed in the early death group (10.8 %). Just 15 (9.6 %) of those linked to care had started ART within 6 months, but 123 (89.1 %) of patients documented to be ART eligible by local guidelines had started ART by the end of 3.5 years. On multivariate analysis, male gender (OR 1.72; 95 % CI 1.08, 2.75), testing due to illness (OR 1.63; 95 % CI 1.01, 2.63), and higher mean depression scale scores (4 % increased risk per increase in depression score; 95 % CI 1 %, 8 %) were associated with early death. Testing at a community versus a hospital-based site (OR 2.89; 95 % CI 1.79, 4.66) was strongly associated with delaying or never entering care. Conclusions Nearly 30 % of the cohort did not have timely care linkage, ART initiation was frequently delayed, and testing at a hospital outpatient department versus community-based testing centers was strongly associated with successful care linkage

HIV serostatus disclosure in the treatment cascade: evidence from Northern Tanzania

ABSTRACTHIV serostatus disclosure plays an important role in HIV transmission risk reduction and is positively associated with HIV medication adherence and treatment outcomes. However, to date, no study has quantified the role of disclosure across the HIV treatment cascade, particularly in Sub-Saharan Africa. We used data from a cohort of HIV-infected adults in Northern Tanzania to describe associations between disclosure and engagement and retention in the HIV treatment cascade. Between 2008 and 2009, the Coping with HIV/AIDS in Tanzania (CHAT) study enrolled 260 clients newly diagnosed with HIV and 492 HIV-infected patients in established HIV care in two large HIV care and treatment centers in Northern Tanzania. Participants aged 18 and older completed annual clinical assessments and twice-annual in-person interviews for 3.5 years. Using logistic regression models, we assessed sociodemographic correlates of HIV serostatus disclosure to at least one household member, and associations between this disclosure measure and linkage to care, evaluation for antiretroviral therapy (ART) eligibility, ART coverage, and rates of undetectable HIV RNA levels during the follow-up period. Married individuals and those diagnosed earlier were more likely to have disclosed their HIV infection to at least one household member. During follow-up, HIV serostatus disclosure was associated with higher rates of linkage to care, evaluation for ART eligibility, and ART coverage. No significant association was observed with rates of undetectable viral loads. Marginal effects estimates suggest that a 10 percentage-point lower probability of linkage to care for those who did not disclose their HIV serostatus (86% vs. 96%; p = 0.035) was compounded by an 18 percentage-point lower probability of ever receiving a CD4 count (62% vs. 80%; p = .039), and a 20 percentage-point lower probability of ever receiving ART (55% vs. 75%; p = .029). If causal, these findings suggest an important role for disclosure assistance efforts across the HIV treatment cascade