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Abstract We construct a polygenic health index as a weighted sum of polygenic risk scores for 20 major disease conditions, including, e.g., coronary artery disease, type 1 and 2 diabetes, schizophrenia, etc. Individual weights are determined by population-level estimates of impact on life expectancy. We validate this index in odds ratios and selection experiments using unrelated individuals and siblings (pairs and trios) from the UK Biobank. Individuals with higher index scores have decreased disease risk across almost all 20 diseases (no significant risk increases), and longer calculated life expectancy. When estimated Disability Adjusted Life Years (DALYs) are used as the performance metric, the gain from selection among ten individuals (highest index score vs average) is found to be roughly 4 DALYs. We find no statistical evidence for antagonistic trade-offs in risk reduction across these diseases. Correlations between genetic disease risks are found to be mostly positive and generally mild. These results have important implications for public health and also for fundamental issues such as pleiotropy and genetic architecture of human disease conditions.

Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.

Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.

Charlotte Laurent,1,2 Sheng Chiong Hong,3,4 Kirsten R Cheyne,2 Kelechi C Ogbuehi2 1Ophthalmology Department, Southern District Health Board, Dunedin, New Zealand; 2University of Otago, Dunedin, New Zealand; 3Ophthalmology Department, Mid Central District Health Board, Palmerston North, New Zealand; 4oDocs Eye Care Limited, Auckland, New ZealandCorrespondence: Charlotte LaurentOphthalmology Department, Dunedin Public Hospital, 201 Great King Street, Dunedin 9016, New ZealandTel +64 21 265 4347Email charlotteclairelaurent@gmail.comPurpose: Spontaneous venous pulsation (SVP) has a high negative predictive value for raised intracranial pressure and is a useful sign when assessing patients with headache. The objective was to determine if smartphone-based video ophthalmoscopy can detect SVP.Patients and Methods: In total 233 patients and 291 eyes were recruited from the Dunedin Hospital eye clinic from July to November 2018. Patients were examined by a clinician and graded for SVP with a slit lamp and 78 Dioptre lens. Videos were taken with a smartphone ophthalmoscope and graded by two separate clinicians blinded to the slit lamp findings.Results: Only 272 eyes of 215 patients were included, as others failed in the inclusion criteria for overall video quality. Sensitivity was calculated as how likely the presence of SVP on video was indicative of the presence of SVP on slit lamp. Sensitivity was 84.77% for Observer 1, with 128 videos graded as positive for SVP on video ophthalmoscopy of the 151 identified as positive on slit lamp examination. Sensitivity was 76.82% for Observer 2 with 116 videos correctly identified. The false positive rate was calculated as the number of videos graded positive for SVP that had been graded as negative on slit lamp examination. This was 10.74% for observer 1 and 31.40% for observer 2.Conclusion: This study demonstrates that SVP is detected by video ophthalmoscopy. This may be a useful triage, telemedicine and referral tool to be used for patients with headache in a primary care setting.Keywords: technology, telemedicine, neurology, headache

Abstract We construct risk predictors using polygenic scores (PGS) computed from common Single Nucleotide Polymorphisms (SNPs) for a number of complex disease conditions, using L1-penalized regression (also known as LASSO) on case-control data from UK Biobank. Among the disease conditions studied are Hypothyroidism, (Resistant) Hypertension, Type 1 and 2 Diabetes, Breast Cancer, Prostate Cancer, Testicular Cancer, Gallstones, Glaucoma, Gout, Atrial Fibrillation, High Cholesterol, Asthma, Basal Cell Carcinoma, Malignant Melanoma, and Heart Attack. We obtain values for the area under the receiver operating characteristic curves (AUC) in the range ~0.58–0.71 using SNP data alone. Substantially higher predictor AUCs are obtained when incorporating additional variables such as age and sex. Some SNP predictors alone are sufficient to identify outliers (e.g., in the 99th percentile of polygenic score, or PGS) with 3–8 times higher risk than typical individuals. We validate predictors out-of-sample using the eMERGE dataset, and also with different ancestry subgroups within the UK Biobank population. Our results indicate that substantial improvements in predictive power are attainable using training sets with larger case populations. We anticipate rapid improvement in genomic prediction as more case-control data become available for analysis.

3D imaging data necessitate 3D reference atlases for accurate quantitative interpretation. Existing computational methods to generate 3D atlases from 2D-derived atlases result in extensive artifacts, while manual curation approaches are labor-intensive. We present a computational approach for 3D atlas construction that substantially reduces artifacts by identifying anatomical boundaries in the underlying imaging data and using these to guide 3D transformation. Anatomical boundaries also allow extension of atlases to complete edge regions. Applying these methods to the eight developmental stages in the Allen Developing Mouse Brain Atlas (ADMBA) led to more comprehensive and accurate atlases. We generated imaging data from 15 whole mouse brains to validate atlas performance and observed qualitative and quantitative improvement (37% greater alignment between atlas and anatomical boundaries). We provide the pipeline as the MagellanMapper software and the eight 3D reconstructed ADMBA atlases. These resources facilitate whole-organ quantitative analysis between samples and across development.

Spherical neutron polarimetry (SNP) experiment in conjunction with high pressure condition faces many experimental difficulties. Here the authors report development of SNP with nonmagnetic hybrid anvil high pressure cell and application to the magnetoelectric multiferroic delafossite CuFeO2 system.

For over 2 decades preimplantation genetic testing (PGT) has been in clinical use to reduce the risk of miscarriage and genetic disease in patients with advanced maternal age and risk of transmitting disease. Recently developed methods of genome-wide genotyping and machine learning algorithms now offer the ability to genotype embryos for polygenic disease risk with accuracy equivalent to adults. In addition, contemporary studies on adults indicate the ability to predict polygenic disorders with risk equivalent to monogenic disorders. Existing biobanks provide opportunities to model the clinical utility of polygenic disease risk reduction among sibling adults. Here, we provide a mathematical model for the use of embryo screening to reduce the risk of type 1 diabetes. Results indicate a 45–72% reduced risk with blinded genetic selection of one sibling. The first clinical case of polygenic risk scoring in human preimplantation embryos from patients with a family history of complex disease is reported. In addition to these data, several common and accepted practices place PGT for polygenic disease risk in the applicable context of contemporary reproductive medicine. In addition, prediction of risk for PCOS, endometriosis, and aneuploidy are of particular interest and relevance to patients with infertility and represent an important focus of future research on polygenic risk scoring in embryos.

Rivers provide a major pathway for ocean plastic waste, but effective mitigation is dependent on a quantification of active sources. Here, the authors present a global model of riverine plastic inputs, and estimate annual plastic waste of almost 2.5 million tonnes, with 86% sourced from Asia.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21077-8.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21052-3

The present study aims to quantify the potential of hyperspectral thermal infrared sounders such as the Infrared Atmospheric Sounding Interferometer (IASI) and the future IASI next generation (IASI-NG) for retrieving the ice cloud layer altitude and thickness together with the ice water path. We employed the radiative transfer model Radiative Transfer for TOVS (RTTOV) to simulate cloudy radiances using parameterized ice cloud optical properties. The radiances have been computed from an ice cloud profile database coming from global operational short-range forecasts at the European Center for Medium-range Weather Forecasts (ECMWF) which encloses the normal conditions, typical variability, and extremes of the atmospheric properties over one year (Eresmaa and McNally (2014)). We performed an information content analysis based on Shannon’s formalism to determine the amount and spectral distribution of the information about ice cloud properties. Based on this analysis, a retrieval algorithm has been developed and tested on the profile database. We considered the signal-to-noise ratio of each specific instrument and the non-retrieved atmospheric and surface parameter errors. This study brings evidence that the observing system provides information on the ice water path (IWP) as well as on the layer altitude and thickness with a convergence rate up to 95% and expected errors that decrease with cloud opacity until the signal saturation is reached (satisfying retrievals are achieved for clouds whose IWP is between about 1 and 300 g/m2).

Structural variants (SVs) are prevalent in genomes of the general population. Here, Guryev and The Genome of the Netherlands Consortium describe the reference panel of haplotype-resolved SVs from 769 individuals from 250 Dutch families and show its utility for studying heritable traits.

FORUM (Far-infrared Outgoing Radiation Understanding and Monitoring) has been approved to be the ninth Earth Explorer mission of the European Space Agency. The mission is scheduled for launch on a Polar satellite in the 2025–2026 time frame. The core FORUM instrument is a Fourier Transform Spectrometer measuring, with very high accuracy, the upwelling spectral radiance, from 100 to 1600 cm − 1 (from 100 to 6.25 microns in wavelength), thus covering the Far-Infrared (FIR), and a Mid-Infrared (MIR) portion of the spectrum emitted by the Earth. FORUM will fly in loose formation with the MetOp-SG-1A satellite, hosting the Infrared Atmospheric Sounding Interferometer – New Generation (IASI-NG). IASI-NG will measure only the MIR part of the upwelling atmospheric spectrum, from 645 to 2760 cm − 1 (from 15.5 to 3.62 microns in wavelength), thus, the matching FORUM measurements will supply the missing FIR complement. Together, the two missions will provide, for the first time, a spectrally resolved measurement of the full Earth emitted thermal spectrum. The calibrated spectral radiance will be, on its own, the main product of the FORUM mission, however, the radiances will also be processed up to Level 2, to determine the vertical profile of water vapour, surface spectral emissivity and cloud parameters in the case of cloudy atmospheres. In this paper we assess the performance of the FORUM Level 2 products based on clear-sky simulated retrievals and we study how the FORUM and IASI-NG matching measurements can be fused in a synergistic retrieval scheme, to provide improved Level 2 products. Considering only the measurement noise and the systematic calibration error components, we find the following figures for the synergistic FORUM and IASI-NG retrieval products. In the upper troposphere/lower stratosphere region, individual water vapour profiles can be retrieved with 1 km vertical sampling and an error ranging from 10% to 15%. In the range from 300 to 600 cm − 1 , surface spectral emissivity can be retrieved with an absolute error as small as 0.001 in dry Polar atmospheres. Ice cloud parameters such as ice water path and cloud top height can be retrieved with errors smaller than 10% and 1 km, respectively, for ice water path values ranging from 0.2 to 60 g/m 2 .

Plastic pollution is ubiquitous throughout the marine environment, yet estimates of the global abundance and weight of floating plastics have lacked data, particularly from the Southern Hemisphere and remote regions. Here we report an estimate of the total number of plastic particles and their weight floating in the world's oceans from 24 expeditions (2007-2013) across all five sub-tropical gyres, costal Australia, Bay of Bengal and the Mediterranean Sea conducting surface net tows (N = 680) and visual survey transects of large plastic debris (N = 891). Using an oceanographic model of floating debris dispersal calibrated by our data, and correcting for wind-driven vertical mixing, we estimate a minimum of 5.25 trillion particles weighing 268,940 tons. When comparing between four size classes, two microplastic 4.75 mm, a tremendous loss of microplastics is observed from the sea surface compared to expected rates of fragmentation, suggesting there are mechanisms at play that remove

Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669-673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans.

The major histocompatibility complex (MHC) is one of the most variable and gene-dense regions of the human genome. Most studies of the MHC, and associated regions, focus on minor variants and HLA typing, many of which have been demonstrated to be associated with human disease susceptibility and metabolic pathways. However, the detection of variants in the MHC region, and diagnostic HLA typing, still lacks a coherent, standardized, cost effective and high coverage protocol of clinical quality and reliability. In this paper, we presented such a method for the accurate detection of minor variants and HLA types in the human MHC region, using high-throughput, high-coverage sequencing of target regions. A probe set was designed to template upon the 8 annotated human MHC haplotypes, and to encompass the 5 megabases (Mb) of the extended MHC region. We deployed our probes upon three, genetically diverse human samples for probe set evaluation, and sequencing data show that ∼97% of the MHC region, and over 99% of the genes in MHC region, are covered with sufficient depth and good evenness. 98% of genotypes called by this capture sequencing prove consistent with established HapMap genotypes. We have concurrently developed a one-step pipeline for calling any HLA type referenced in the IMGT/HLA database from this target capture sequencing data, which shows over 96% typing accuracy when deployed at 4 digital resolution. This cost-effective and highly accurate approach for variant detection and HLA typing in the MHC region may lend further insight into immune-mediated diseases studies, and may find clinical utility in transplantation medicine research. This one-step pipeline is released for general evaluation and use by the scientific community.

Down syndrome (DS) is a developmental disorder associated with mental retardation (MR) and early onset Alzheimer's disease (AD). These CNS phenotypes are attributed to ongoing neuronal degeneration due to constitutive overexpression of chromosome 21 (HSA21) genes. We have previously shown that HSA21 associated S100B contributes to oxidative stress and apoptosis in DS human neural progenitors (HNPs). Here we show that DS HNPs isolated from fetal frontal cortex demonstrate not only disturbances in redox states within the mitochondria and increased levels of progenitor cell death but also transition to more gliocentric progenitor phenotypes with a consequent reduction in neuronogenesis. HSA21 associated S100B and amyloid precursor protein (APP) levels are simultaneously increased within DS HNPs, their secretions are synergistically enhanced in a paracrine fashion, and overexpressions of these proteins disrupt mitochondrial membrane potentials and redox states. HNPs show greater susceptibility to these proteins as compared to neurons, leading to cell death. Ongoing inflammation through APP and S100B overexpression further promotes a gliocentric HNPs phenotype. Thus, the loss in neuronal numbers seen in DS is not merely due to increased HNPs cell death and neurodegeneration, but also a fundamental gliocentric shift in the progenitor pool that impairs neuronal production.

Calcium imaging using fluorescent reporters is the most widely used optical approach to investigate activity in intact neuronal circuits with single-cell resolution. Calcium signals, however, are often difficult to interpret, especially if the desired output quantity is membrane voltage or instantaneous firing rates. Combining dendritic intracellular electrophysiology and multi-photon calcium imaging in vivo, we recently investigated the relationship between optical signals recorded with the fluorescent calcium indicator Oregon Green BAPTA-1 (OGB-1) and spike output in principal neurons in the locust antennal lobe. We derived from these experiments a simple, empirical and easily adaptable method requiring minimal calibration to reconstruct firing rates from calcium signals with good accuracy and 50-ms temporal resolution.

Combining intracellular electrophysiology and multi-photon calcium imaging in vivo, we studied the relationship between calcium signals (sampled at 500-750 Hz) and spike output in principal neurons in the locust antennal lobe. Our goal was to determine whether the firing rate of individual neurons can be estimated in vivo with calcium imaging and, if so, to measure directly the accuracy and resolution of our estimates. Using the calcium indicator Oregon Green BAPTA-1, we describe a simple method to reconstruct firing rates from dendritic calcium signals with 80-90% accuracy and 50ms temporal resolution.

In the last decade rare-earth hexaborides have been investigated for their fundamental importance in condensed matter, and for their applications in advanced technological fields. Among these compounds, LaB6 has a special place, being a traditional d-band metal without additional f bands. In order to understand the bulk electronic structure of the more complex rare-earth hexaborides, in this paper we investigate the bulk electronic structure of LaB6 using tender/hard x-ray photoemission spectroscopy, measuring both core-level and angle-resolved valence-band spectra. Furthermore, we compare the La 3d core level spectrum to cluster model calculations in order to understand the bulklike core-hole screening effects. The results show that the La 3d well-screened peak is at a lower binding energy compared to the main poorly screened peak; the relative intensity between these peaks depends on how strong the hybridization is between La and B atoms. We show that the recoil effect, negligible in the soft x-ray regime, becomes prominent at higher kinetic energies for lighter elements, such as boron, but is still negligible for heavy elements, such as lanthanum. In addition, we report the bulklike band structure of LaB6 determined by tender/hard x-ray angle-resolved photoemission spectroscopy (HARPES). We compare HARPES experimental results to the free-electron final-state calculations and to the more precise one-step photoemission theory including matrix element and phonon excitation effects. The agreement between the features present in the experimental ARPES data and the theoretical calculations is very good. In addition, we consider the nature and the magnitude of phonon excitations in order to interpret HARPES experimental data measured at different temperatures and excitation energies. We demonstrate that the one-step theory of photoemission and HARPES experiments provides, at present, the only approach capable of probing, both experimentally and theoretically, true "bulklike"electronic band structure of rare-earth hexaborides and strongly correlated materials.

3D imaging data necessitate 3D reference atlases for accurate quantitative interpretation. Existing computational methods to generate 3D atlases from 2D-derived atlases result in extensive artifacts, while manual curation approaches are labor-intensive. We present a computational approach for 3D atlas construction that substantially reduces artifacts by identifying anatomical boundaries in the underlying imaging data and using these to guide 3D transformation. Anatomical boundaries also allow extension of atlases to complete edge regions. Applying these methods to the eight developmental stages in the Allen Developing Mouse Brain Atlas (ADMBA) led to more comprehensive and accurate atlases. We generated imaging data from 15 whole mouse brains to validate atlas performance and observed qualitative and quantitative improvement (37% greater alignment between atlas and anatomical boundaries). We provide the pipeline as the MagellanMapper software and the eight 3D reconstructed ADMBA atlases. These resources facilitate whole-organ quantitative analysis between samples and across development.

We propose a new paradigm for dense functional imaging of brain activity to surmount the limitations of present methodologies. We term this approach "integrated neurophotonics"; it combines recent advances in microchip-based integrated photonic and electronic circuitry with those from optogenetics. This approach has the potential to enable lens-less functional imaging from within the brain itself to achieve dense, large-scale stimulation and recording of brain activity with cellular resolution at arbitrary depths. We perform a computational study of several prototype 3D architectures for implantable probe-array modules that are designed to provide fast and dense single-cell resolution (e.g., within a 1-mm3 volume of mouse cortex comprising ∼100,000 neurons). We describe progress toward realizing integrated neurophotonic imaging modules, which can be produced en masse with current semiconductor foundry protocols for chip manufacturing. Implantation of multiple modules can cover extended brain regions.

Transition-metal dichalcogenides (TMDs) offer an ideal platform to experimentally realize Dirac fermions. However, typically these exotic quasiparticles are located far away from the Fermi level, limiting the contribution of Dirac-like carriers to the transport properties. Here we show that NiTe2 hosts both bulk Type-II Dirac points and topological surface states. The underlying mechanism is shared with other TMDs and based on the generic topological character of the Te p-orbital manifold. However, unique to NiTe2, a significant contribution of Ni d orbital states shifts the energy of the Type-II Dirac point close to the Fermi level. In addition, one of the topological surface states intersects the Fermi energy and exhibits a remarkably large spin splitting of 120 meV. Our results establish NiTe2 as an exciting candidate for next-generation spintronics devices.

Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

Vibrationally-resolved resonant inelastic X-ray scattering (VR-RIXS) at the O K-edge is emerging as a powerful tool for identifying embedded molecules in lithium-ion battery cathodes. Here, we investigate two known oxygen redox-active cathode materials: the commercial LixNi0.90Co0.05Al0.05O2 (NCA) used in electric vehicles and the high-capacity cathode material Li1.2Ni0.13Co0.13Mn0.54O2 (LRNMC) for next-generation Li-ion batteries. We report the detection of a novel vibrational RIXS signature for Li-ion battery cathodes appearing in the O K pre-peak above 533 eV that we attribute to OH-groups. We discuss likely locations and pathways for OH-group formation and accumulation throughout the active cathode material. Initial-cycle behaviour for LRNMC shows that OH-signal strength correlates with the cathodes state of charge, though reversibility is incomplete. The OH-group RIXS signal strength in long-term cycled NCA is retained. Thus, VR-RIXS offers a path for gaining new insights to oxygen reactions in battery materials. [ABSTRACT FROM AUTHOR]