Time- and region-dependent blood-brain barrier impairment in a rat model of organophosphate-induced status epilepticus

Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication

A Human Depression Circuit Derived From Focal Brain Lesions

Background: Focal brain lesions can lend insight into the causal neuroanatomical substrate of depression in the human brain. However, studies of lesion location have led to inconsistent results.Methods: Five independent datasets with different lesion etiologies and measures of postlesion depression were collated (N = 461). Each 3-dimensional lesion location was mapped to a common brain atlas. We used voxel lesion symptom mapping to test for associations between depression and lesion locations. Next, we computed the network of regions functionally connected to each lesion location using a large normative connectome dataset (N = 1000). We used these lesion network maps to test for associations between depression and connected brain circuits. Reproducibility was assessed using a rigorous leave-one-dataset-out validation. Finally, we tested whether lesion locations associated with depression fell within the same circuit as brain stimulation sites that were effective for improving poststroke depression.Results: Lesion locations associated with depression were highly heterogeneous, and no single brain region was consistently implicated. However, these same lesion locations mapped to a connected brain circuit, centered on the left dorsolateral prefrontal cortex. Results were robust to leave-one-dataset-out cross-validation. Finally, our depression circuit derived from brain lesions aligned with brain stimulation sites that were effective for improving poststroke depression.Conclusions: Lesion locations associated with depression fail to map to a specific brain region but do map to a specific brain circuit. This circuit may have prognostic utility in identifying patients at risk for poststroke depression and therapeutic utility in refining brain stimulation targets.</p

Exploring movement patterns and changing distributions of baleen whales in the western North Atlantic using a decade of passive acoustic data

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Davis, G. E., Baumgartner, M. F., Corkeron, P. J., Bell, J., Berchok, C., Bonnell, J. M., Thornton, J. B., Brault, S., Buchanan, G. A., Cholewiak, D. M., Clark, C. W., Delarue, J., Hatch, L. T., Klinck, H., Kraus, S. D., Martin, B., Mellinger, D. K., Moors-Murphy, H., Nieukirk, S., Nowacek, D. P., Parks, S. E., Parry, D., Pegg, N., Read, A. J., Rice, A. N., Risch, D., Scott, A., Soldevilla, M. S., Stafford, K. M., Stanistreet, J. E., Summers, E., Todd, S., & Van Parijs, S. M. Exploring movement patterns and changing distributions of baleen whales in the western North Atlantic using a decade of passive acoustic data. Global Change Biology, (2020): 1-30, doi:10.1111/gcb.15191.Six baleen whale species are found in the temperate western North Atlantic Ocean, with limited information existing on the distribution and movement patterns for most. There is mounting evidence of distributional shifts in many species, including marine mammals, likely because of climate‐driven changes in ocean temperature and circulation. Previous acoustic studies examined the occurrence of minke (Balaenoptera acutorostrata ) and North Atlantic right whales (NARW; Eubalaena glacialis ). This study assesses the acoustic presence of humpback (Megaptera novaeangliae ), sei (B. borealis ), fin (B. physalus ), and blue whales (B. musculus ) over a decade, based on daily detections of their vocalizations. Data collected from 2004 to 2014 on 281 bottom‐mounted recorders, totaling 35,033 days, were processed using automated detection software and screened for each species' presence. A published study on NARW acoustics revealed significant changes in occurrence patterns between the periods of 2004–2010 and 2011–2014; therefore, these same time periods were examined here. All four species were present from the Southeast United States to Greenland; humpback whales were also present in the Caribbean. All species occurred throughout all regions in the winter, suggesting that baleen whales are widely distributed during these months. Each of the species showed significant changes in acoustic occurrence after 2010. Similar to NARWs, sei whales had higher acoustic occurrence in mid‐Atlantic regions after 2010. Fin, blue, and sei whales were more frequently detected in the northern latitudes of the study area after 2010. Despite this general northward shift, all four species were detected less on the Scotian Shelf area after 2010, matching documented shifts in prey availability in this region. A decade of acoustic observations have shown important distributional changes over the range of baleen whales, mirroring known climatic shifts and identifying new habitats that will require further protection from anthropogenic threats like fixed fishing gear, shipping, and noise pollution.We thank Chris Pelkie, David Wiley, Michael Thompson, Chris Tessaglia‐Hymes, Eric Matzen, Chris Tremblay, Lance Garrison, Anurag Kumar, John Hildebrand, Lynne Hodge, Russell Charif, Kathleen Dudzinski, and Ann Warde for help with project planning, field work support, and data management. For all the support and advice, thanks to the NEFSC Protected Species Branch, especially the passive acoustics group, Josh Hatch, and Leah Crowe. We thank the field and crew teams on all the ships that helped in the numerous deployments and recoveries. This research was funded and supported by many organizations, specified by projects as follows: data recordings from region 1 were provided by K. Stafford (funding: National Science Foundation #NSF‐ARC 0532611). Region 2 data: D. K. Mellinger and S. Nieukirk, National Oceanic and Atmospheric Administration (NOAA) PMEL contribution #5055 (funding: NOAA and the Office of Naval Research #N00014–03–1–0099, NOAA #NA06OAR4600100, US Navy #N00244‐08‐1‐0029, N00244‐09‐1‐0079, and N00244‐10‐1‐0047). Region 3A data: D. Risch (funding: NOAA and Navy N45 programs). Region 3 data: H. Moors‐Murphy and Fisheries and Oceans Canada (2005–2014 data), and the Whitehead Lab of Dalhousie University (eastern Scotian Shelf data; logistical support by A. Cogswell, J. Bartholette, A. Hartling, and vessel CCGS Hudson crew). Emerald Basin and Roseway Basin Guardbuoy data, deployment, and funding: Akoostix Inc. Region 3 Emerald Bank and Roseway Basin 2004 data: D. K. Mellinger and S. Nieukirk, NOAA PMEL contribution #5055 (funding: NOAA). Region 4 data: S. Parks (funding: NOAA and Cornell University) and E. Summers, S. Todd, J. Bort Thornton, A. N. Rice, and C. W. Clark (funding: Maine Department of Marine Resources, NOAA #NA09NMF4520418, and #NA10NMF4520291). Region 5 data: S. M. Van Parijs, D. Cholewiak, L. Hatch, C. W. Clark, D. Risch, and D. Wiley (funding: National Oceanic Partnership Program (NOPP), NOAA, and Navy N45). Region 6 data: S. M. Van Parijs and D. Cholewiak (funding: Navy N45 and Bureau of Ocean and Energy Management (BOEM) Atlantic Marine Assessment Program for Protected Species [AMAPPS] program). Region 7 data: A. N. Rice, H. Klinck, A. Warde, B. Martin, J. Delarue, and S. Kraus (funding: New York State Department of Environmental Conservation, Massachusetts Clean Energy Center, and BOEM). Region 8 data: G. Buchanan, and K. Dudzinski (funding: New Jersey Department of Environmental Protection and the New Jersey Clean Energy Fund) and A. N. Rice, C. W. Clark, and H. Klinck (funding: Center for Conservation Bioacoustics at Cornell University and BOEM). Region 9 data: J. E. Stanistreet, J. Bell, D. P. Nowacek, A. J. Read, and S. M. Van Parijs (funding: NOAA and US Fleet Forces Command). Region 10 data: L. Garrison, M. Soldevilla, C. W. Clark, R. A. Chariff, A. N. Rice, H. Klinck, J. Bell, D. P. Nowacek, A. J. Read, J. Hildebrand, A. Kumar, L. Hodge, and J. E. Stanistreet (funding: US Fleet Forces Command, BOEM, NOAA, and NOPP). Region 11 data: C. Berchok as part of a collaborative project led by the Fundacion Dominicana de Estudios Marinos, Inc. (Dr. Idelisa Bonnelly de Calventi; funding: The Nature Conservancy [Elianny Dominguez]) and D. Risch (funding: World Wildlife Fund, NOAA, and Dutch Ministry of Economic Affairs)

Landsat 9 Thermal Infrared Sensor 2 Architecture and Design

The Thermal Infrared Sensor 2 (TIRS-2) will fly aboard the Landsat 9 spacecraft and leverages the Thermal Infrared Sensor (TIRS) design currently flying on Landsat 8. TIRS-2 will provide similar science data as TIRS, but is not a buildto-print rebuild due to changes in requirements and improvements in absolute accuracy. The heritage TIRS design has been modified to reduce the influence of stray light and to add redundancy for higher reliability over a longer mission life. The TIRS-2 development context differs from the TIRS scenario, adding to the changes. The TIRS-2 team has also learned some lessons along the way

Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study

BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged &lt;65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown.ObjectiveThis study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD.MethodsParticipants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age.ResultsThe CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P&lt;.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P&lt;.001 in all cases).ConclusionsThese findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change

Identifying Treatments for Taste and Smell Disorders: Gaps and Opportunities.

The chemical senses of taste and smell play a vital role in conveying information about ourselves and our environment. Tastes and smells can warn against danger and also contribute to the daily enjoyment of food, friends and family, and our surroundings. Over 12% of the US population is estimated to experience taste and smell (chemosensory) dysfunction. Yet, despite this high prevalence, long-term, effective treatments for these disorders have been largely elusive. Clinical successes in other sensory systems, including hearing and vision, have led to new hope for developments in the treatment of chemosensory disorders. To accelerate cures, we convened the Identifying Treatments for Taste and Smell Disorders conference, bringing together basic and translational sensory scientists, health care professionals, and patients to identify gaps in our current understanding of chemosensory dysfunction and next steps in a broad-based research strategy. Their suggestions for high-yield next steps were focused in 3 areas: increasing awareness and research capacity (e.g., patient advocacy), developing and enhancing clinical measures of taste and smell, and supporting new avenues of research into cellular and therapeutic approaches (e.g., developing human chemosensory cell lines, stem cells, and gene therapy approaches). These long-term strategies led to specific suggestions for immediate research priorities that focus on expanding our understanding of specific responses of chemosensory cells and developing valuable assays to identify and document cell development, regeneration, and function. Addressing these high-priority areas should accelerate the development of novel and effective treatments for taste and smell disorders

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine