A Hybrid Architecture (CO-CONNECT) to Facilitate Rapid Discovery and Access to Data Across the United Kingdom in Response to the COVID-19 Pandemic: Development Study.

BACKGROUND: COVID-19 data have been generated across the United Kingdom as a by-product of clinical care and public health provision, as well as numerous bespoke and repurposed research endeavors. Analysis of these data has underpinned the United Kingdom's response to the pandemic, and informed public health policies and clinical guidelines. However, these data are held by different organizations, and this fragmented landscape has presented challenges for public health agencies and researchers as they struggle to find relevant data to access and interrogate the data they need to inform the pandemic response at pace. OBJECTIVE: We aimed to transform UK COVID-19 diagnostic data sets to be findable, accessible, interoperable, and reusable (FAIR). METHODS: A federated infrastructure model (COVID - Curated and Open Analysis and Research Platform [CO-CONNECT]) was rapidly built to enable the automated and reproducible mapping of health data partners' pseudonymized data to the Observational Medical Outcomes Partnership Common Data Model without the need for any data to leave the data controllers' secure environments, and to support federated cohort discovery queries and meta-analysis. RESULTS: A total of 56 data sets from 19 organizations are being connected to the federated network. The data include research cohorts and COVID-19 data collected through routine health care provision linked to longitudinal health care records and demographics. The infrastructure is live, supporting aggregate-level querying of data across the United Kingdom. CONCLUSIONS: CO-CONNECT was developed by a multidisciplinary team. It enables rapid COVID-19 data discovery and instantaneous meta-analysis across data sources, and it is researching streamlined data extraction for use in a Trusted Research Environment for research and public health analysis. CO-CONNECT has the potential to make UK health data more interconnected and better able to answer national-level research questions while maintaining patient confidentiality and local governance procedures.

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

Ground-level Unmanned Aerial System Imagery Coupled with Spatially Balanced Sampling and Route Optimization to Monitor Rangeland Vegetation.

Rangeland ecosystems cover 3.6 billion hectares globally with 239 million hectares located in the United States. These ecosystems are critical for maintaining global ecosystem services. Monitoring vegetation in these ecosystems is required to assess rangeland health, to gauge habitat suitability for wildlife and domestic livestock, to combat invasive weeds, and to elucidate temporal environmental changes. Although rangeland ecosystems cover vast areas, traditional monitoring techniques are often time-consuming and cost-inefficient, subject to high observer bias, and often lack adequate spatial information. Image-based vegetation monitoring is faster, produces permanent records (i.e., images), may result in reduced observer bias, and inherently includes adequate spatial information. Spatially balanced sampling designs are beneficial in monitoring natural resources. A protocol is presented for implementing a spatially balanced sampling design known as balanced acceptance sampling (BAS), with imagery acquired from ground-level cameras and unmanned aerial systems (UAS). A route optimization algorithm is used in addition to solve the 'travelling salesperson problem' (TSP) to increase time and cost efficiency. While UAS images can be acquired 2-3x faster than handheld images, both types of images are similar to each other in terms of accuracy and precision. Lastly, the pros and cons of each method are discussed and examples of potential applications for these methods in other ecosystems are provided.

Aerial and terrestrial-based monitoring of channel erosion, headcutting, and sinuosity.

Headcuts are points of accelerated channel erosion that frequently have ecological consequences. A particularly large and dynamic headcut in southwest Wyoming has affected natural and anthropogenic resources for decades. To better understand and address this issue, we undertook a review of the headcut's upstream retreat, followed by photogrammetric monitoring of the present condition for erosion monitoring. Aerial photography shows the Bitter Creek headcut retreated > 200 m upstream in 68 years (1948-2016) at ~ 1.4 m year-1. Following installation of a concrete slab structure in the mid-1970s, headcut retreat slowed to ~ 0.5 m year-1. Channel sinuosity downstream of the headcut is greater than upstream, which we attribute to the presence of the headcut, given that there are no major changes in valley geometry, geology, or soils through this reach. Both aerial and terrestrial-based image platforms were used to collect stereo imagery and create 3D photogrammetric models of the headcut in 2016. From these two models, we measured soil loss downstream of the headcut at ~ 126 m3 m-1 valley length. Since 1954, soil loss within the channel has been ~ 98 m3 year-1 or ~871 t ha-1 year-1since then. Models created from aerial- and terrestrial-based images differed in volumetric estimates by 2%, indicating that either method could be used for this type of monitoring. The ground-based imagery model showed more detail, especially on vertical and overhanging surfaces, while the aerial imagery model produced a more realistic orthomosaic and efficiently covered a larger area. Ground-based image acquisition took longer and was more costly per unit area, but is an efficient method for small project areas, or areas where aerial imagery cannot be safely or practically acquired. Historical imagery and photogrammetric modeling proved very useful in elucidating stream dynamics associated with this large, dynamic headcut.

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw.

The jaw is central to the extensive variety of feeding and predatory behaviors across vertebrates. The bones of the lower but not upper jaw form around an early-developing cartilage template. Whereas Endothelin1 patterns the lower jaw, the factors that specify upper-jaw morphology remain elusive. Here, we identify Nuclear Receptor 2f genes (Nr2fs) as enriched in and required for upper-jaw formation in zebrafish. Combinatorial loss of Nr2fs transforms maxillary components of the upper jaw into lower-jaw-like structures. Conversely, nr2f5 misexpression disrupts lower-jaw development. Genome-wide analyses reveal that Nr2fs repress mandibular gene expression and early chondrogenesis in maxillary precursors. Rescue of lower-jaw defects in endothelin1 mutants by reducing Nr2f dosage further demonstrates that Nr2f expression must be suppressed for normal lower-jaw development. We propose that Nr2fs shape the upper jaw by protecting maxillary progenitors from early chondrogenesis, thus preserving cells for later osteogenesis.

Headcut Erosion in Wyoming's Sweetwater Subbasin.

Increasing human population and intensive land use combined with a warming climate and chronically diminished snowpacks are putting more strain on water resources in the western United States. Properly functioning riparian systems slow runoff and store water, thus regulating extreme flows; however, riparian areas across the west are in a degraded condition with a majority of riparian systems not in proper functioning condition, and with widespread catastrophic erosion of water-storing peat and organic soils. Headcuts are the leading edge of catastrophic channel erosion. We used aerial imagery (1.4-3.3-cm pixel) to locate 163 headcuts in riparian areas in the Sweetwater subbasin of central Wyoming. We found 1-m-the generally available standard resolution for land management-and 30-cm pixel imagery to be inadequate for headcut identification. We also used Structure-from-Motion models built from ground-acquired imagery to model 18 headcuts from which we measured soil loss of 425-720 m3. Normalized by channel length, this represents a loss of 1.1-1.8 m3 m(-1) channel. Monitoring headcuts, either from ground or aerial imagery, provides an objective indicator of sustainable riparian land management and identifies priority disturbance-mitigation areas. Image-based headcut monitoring must use data on the order of 3.3 cm ground sample distance, or greater resolution, to effectively capture the information needed for accurate assessments of riparian conditions.

An essential role of variant histone H3.3 for ectomesenchyme potential of the cranial neural crest.

The neural crest (NC) is a vertebrate-specific cell population that exhibits remarkable multipotency. Although derived from the neural plate border (NPB) ectoderm, cranial NC (CNC) cells contribute not only to the peripheral nervous system but also to the ectomesenchymal precursors of the head skeleton. To date, the developmental basis for such broad potential has remained elusive. Here, we show that the replacement histone H3.3 is essential during early CNC development for these cells to generate ectomesenchyme and head pigment precursors. In a forward genetic screen in zebrafish, we identified a dominant D123N mutation in h3f3a, one of five zebrafish variant histone H3.3 genes, that eliminates the CNC-derived head skeleton and a subset of pigment cells yet leaves other CNC derivatives and trunk NC intact. Analyses of nucleosome assembly indicate that mutant D123N H3.3 interferes with H3.3 nucleosomal incorporation by forming aberrant H3 homodimers. Consistent with CNC defects arising from insufficient H3.3 incorporation into chromatin, supplying exogenous wild-type H3.3 rescues head skeletal development in mutants. Surprisingly, embryo-wide expression of dominant mutant H3.3 had little effect on embryonic development outside CNC, indicating an unexpectedly specific sensitivity of CNC to defects in H3.3 incorporation. Whereas previous studies had implicated H3.3 in large-scale histone replacement events that generate totipotency during germ line development, our work has revealed an additional role of H3.3 in the broad potential of the ectoderm-derived CNC, including the ability to make the mesoderm-like ectomesenchymal precursors of the head skeleton.

Dual-camera, high-resolution aerial assessment of pipeline revegetation.

Energy-extraction results in significant disturbance to rangelands in Wyoming and other western US states. Although reclamation is required by law, US General Accounting Office reports from 1999 and 2005 are clear that affected government agencies have--over much of the past decade--had difficulty accomplishing mandated environmental monitoring of extraction-related disturbance. We evaluated two pipeline rights of way (ROW) using nested images (1- or 2- with 13- or 20-mm ground sample distance (GSD)) acquired during Very-Large Scale Aerial (VLSA) surveys. Aerial monitoring allowed for the collection of large numbers of geocoded samples, and for subsequent cover measurements using methods with demonstrated accuracy equal to that of conventional ground-based methods. Both pipelines had vegetative-cover deficiencies relative to their Plan of Development (POD) requirements. Using bare ground and ground-cover measurements from the higher-resolution imagery, we present a spatial representation of each pipeline ROW that allows quick identification of sections of the ROW that may need further reclamation action to meet POD standards. We also present aerial monitoring costs. We recommend VLSA pipeline surveys as a means for facilitating required environmental monitoring and for addressing the monitoring backlog that has developed with increased energy-extraction activity.

Shadow attenuation with high dynamic range images. Creating RGB images that allow feature classification in areas otherwise obscured by shadow or oversaturation.

Shadow often interferes with accurate image analysis. To mitigate shadow effects in near-earth imagery (2 m above ground level), we created high dynamic range (HDR) nadir images and used them to measure grassland ground cover. HDR composites were created by merging three differentially exposed images spanning a wide exposure range and resulted in lightened shadows. HDR images showed more detail; reduced the numbers of pure black, pure white, and pixels visually indistinguishable from black and white; reapportioned skewed luma values towards a normal distribution; and increased the Euclidean distance between litter and bare ground RGB values--allowing increased feature separation; all of which facilitated an increase in real feature classification through manual image analysis. Drawbacks to the method included decreased image sharpness due to minor misalignment of images or moving vegetation, time required to create HDR images, and difficulty with acquiring primary images from a moving platform. We conclude that HDR imagery can provide more accurate measurements of bare soil cover for ecosystem monitoring and assessment.

Ground-cover measurements: assessing correlation among aerial and ground-based methods.

Wyoming's Green Mountain Common Allotment is public land providing livestock forage, wildlife habitat, and unfenced solitude, amid other ecological services. It is also the center of ongoing debate over USDI Bureau of Land Management's (BLM) adjudication of land uses. Monitoring resource use is a BLM responsibility, but conventional monitoring is inadequate for the vast areas encompassed in this and other public-land units. New monitoring methods are needed that will reduce monitoring costs. An understanding of data-set relationships among old and new methods is also needed. This study compared two conventional methods with two remote sensing methods using images captured from two meters and 100 meters above ground level from a camera stand (a ground, image-based method) and a light airplane (an aerial, image-based method). Image analysis used SamplePoint or VegMeasure software. Aerial methods allowed for increased sampling intensity at low cost relative to the time and travel required by ground methods. Costs to acquire the aerial imagery and measure ground cover on 162 aerial samples representing 9000 ha were less than $3000. The four highest correlations among data sets for bare ground--the ground-cover characteristic yielding the highest correlations (r)--ranged from 0.76 to 0.85 and included ground with ground, ground with aerial, and aerial with aerial data-set associations. We conclude that our aerial surveys are a cost-effective monitoring method, that ground with aerial data-set correlations can be equal to, or greater than those among ground-based data sets, and that bare ground should continue to be investigated and tested for use as a key indicator of rangeland health.

Point sampling digital imagery with 'SamplePoint'.

Measuring percent occurrence of objects from digital images can save time and expense relative to conventional field measurements. However, the accuracy of image analysis had, until now, not reached the level of the best conventional field measurements. Additionally, most image-analysis software programs require advanced user training to successfully analyze images. Here we present a new software program, 'SamplePoint,' that provides the user a single-pixel sample point and the ability to view and identify the pixel context. We found SamplePoint to allow accuracy comparable with the most accurate field-methods for ground-cover measurements. Expert use of the program requires minimal training and its ease of use allows rapid measurements from image data. We recommend SamplePoint for calibrating the threshold-detection level of image-analysis software or for making direct measurements of percent occurrence from digital images.

Precision measurements from very-large scale aerial digital imagery.

Managers need measurements and resource managers need the length/width of a variety of items including that of animals, logs, streams, plant canopies, man-made objects, riparian habitat, vegetation patches and other things important in resource monitoring and land inspection. These types of measurements can now be easily and accurately obtained from very large scale aerial (VLSA) imagery having spatial resolutions as fine as 1 millimeter per pixel by using the three new software programs described here. VLSA images have small fields of view and are used for intermittent sampling across extensive landscapes. Pixel-coverage among images is influenced by small changes in airplane altitude above ground level (AGL) and orientation relative to the ground, as well as by changes in topography. These factors affect the object-to-camera distance used for image-resolution calculations. 'ImageMeasurement' offers a user-friendly interface for accounting for pixel-coverage variation among images by utilizing a database. 'LaserLOG' records and displays airplane altitude AGL measured from a high frequency laser rangefinder, and displays the vertical velocity. 'Merge' sorts through large amounts of data generated by LaserLOG and matches precise airplane altitudes with camera trigger times for input to the ImageMeasurement database. We discuss application of these tools, including error estimates. We found measurements from aerial images (collection resolution: 5-26 mm/pixel as projected on the ground) using ImageMeasurement, LaserLOG, and Merge, were accurate to centimeters with an error less than 10%. We recommend these software packages as a means for expanding the utility of aerial image data.

Surplus zinc is handled by Zym1 metallothionein and Zhf endoplasmic reticulum transporter in Schizosaccharomyces pombe.

Homeostatic mechanisms prevent the accumulation of free zinc in the cytoplasm, raising questions regarding where surplus zinc is stored and how it is delivered to and from these stores. A genetic screen for zinc hypersensitivity in Schizosaccharomyces pombe identified a missense mutation truncating Zhf, an endoplasmic reticulum transporter. These cells were approximately 5-fold more zinc-sensitive than other independent mutants. The targeted disruption of zhf prevented growth on low zinc medium and caused hypersensitivity to elevated zinc/cobalt but resistance to cadmium. The exposure to elevated zinc but not copper also promotes the accumulation of transcripts encoding a metallothionein designated Zym1. The Sty1 pathway is required for maximal zym1 expression but is not obligatory for zinc perception. The targeted disruption of zym1 impaired cadmium tolerance but only slightly impaired zinc tolerance, whereas zym1 overexpression substantially rescued zinc hypersensitivity of zhf(-) cells. Four equivalents of zinc were displaced from Zym1 by up to 12 equivalents of p-(hydroxymercuri)phenylsulphonate. Zym1 thiols react rapidly with 5,5'-dithiobis-(2-nitrobenzoic acid) compared with bacterial zinc metallothionein (6.8 and 0.2 x 10(-4) s(-1), respectively). Zym1 is unlike known fungal metallothioneins that are induced by and sequester copper but not zinc. Less zinc but normal cadmium was accumulated by zym1Delta, consistent with zinc sequestration by Zym1 in vivo.