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This article presents a physics-based inversion technique for reliable characterization of droplets deposited by a liquid metal jetting additive manufacturing system, using an in-situ millimeter wave diagnostic. The overall approach is demonstrated in a custom droplet-on-demand liquid metal jetting system with effective droplet diameters ranging from 0.8 to 1.7 mm. The inversion results demonstrate that this approach can provide information about the droplet size and lift-off distance between the droplet and the diagnostic by monitoring the amplitude and phase of the reflection coefficient at the input port.

Background: Vasovagal reactions (VVRs) are the most common acute complications of blood donation. Responsible for substantial morbidity, they also reduce the likelihood of repeated donations, and are disruptive and costly for blood services. Although blood establishments worldwide have adopted different strategies to prevent VVRs (including water loading and applied muscle tension [AMT]), robust evidence is limited. The Strategies to Improve Donor Experiences (STRIDES) trial aims to reliably assess the impact of four different interventions to prevent VVRs among blood donors. Methods: STRIDES is a cluster-randomised cross-over/stepped-wedge factorial trial of four interventions to reduce VVRs involving about 1.4 million whole blood donors enrolled from all 73 blood donation sites (mobile teams and donor centres) of National Health Service Blood and Transplant (NHSBT) in England. Each site (“cluster”) has been randomly allocated to receive one or more interventions during a 36-month period, using principles of cross-over, stepped-wedge and factorial trial design to assign the sequence of interventions. Each of the four interventions are compared to NHSBT’s current practices: (i) 500ml isotonic drink before donation vs current 500ml plain water; (ii) 3-minutes rest on donation chair after donation vs current 2 minutes; (iii) new modified AMT vs current practice of AMT; and (iv) psychosocial intervention using preparatory materials vs current practice of nothing. The primary outcome is the number of in-session VVRs with loss of consciousness (i.e., episodes involving loss of consciousness of any duration, with or without additional complications). Secondary outcomes include all in-session VVRs (i.e., with and without loss of consciousness) and delayed VVRs (i.e., those occurring after leaving the venue). Discussion: The STRIDES trial should yield novel information about interventions, singly and in combination, for the prevention of VVRs, with the aim of generating policy-shaping evidence to help inform blood services to improve donor health, donor experience, and service efficiency. Trial registration: ISRCTN: 10412338

Boundary conditions for catalyst performance in the conversion of common precursors such as N2, O2, H2O, and CO2 are governed by linear free energy and scaling relationships. Knowledge of these limits offers an impetus for designing strategies to alter reaction mechanisms to improve performance. Typically, experimental demonstrations of linear trends and deviations from them are composed of a small number of data points constrained by inherent experimental limitations. Herein, high-throughput experimentation on 14 bulk copper bimetallic alloys allowed for data-driven identification of a scaling relationship between the partial current densities of methane and C2+ products. This strict dependence represents an intrinsic limit to the Faradaic efficiency for C–C coupling. We have furthermore demonstrated that coating the electrodes with a molecular film breaks the scaling relationship to promote C2+ product formation., High-throughput experimentation on the reduction of CO2 on copper alloys led to the identification of a scaling relationship between CH4 and C2+ products that can be broken with an organic additive.

We describe results of testing blood donors in London, UK, for severe acute respiratory disease coronavirus 2 (SARS-CoV-2) IgG before and after lockdown measures. Anonymized samples from donors 17-69 years of age were tested using 3 assays: Euroimmun IgG, Abbott IgG, and an immunoglobulin receptor-binding domain assay developed by Public Health England. Seroprevalence increased from 3.0% prelockdown (week 13, beginning March 23, 2020) to 10.4% during lockdown (weeks 15-16) and 12.3% postlockdown (week 18) by the Abbott assay. Estimates were 2.9% prelockdown, 9.9% during lockdown, and 13.0% postlockdown by the Euroimmun assay and 3.5% prelockdown, 11.8% during lockdown, and 14.1% postlockdown by the receptor-binding domain assay. By early May 2020, nearly 1 in 7 donors had evidence of past SARS-CoV-2 infection. Combining results from the Abbott and Euroimmun assays increased seroprevalence by 1.6%, 2.3%, and 0.6% at the 3 timepoints compared with Euroimmun alone, demonstrating the value of using multiple assays.

Between 7 and 25 May, 86 monkeypox cases were confirmed in the United Kingdom (UK). Only one case is known to have travelled to a monkeypox virus (MPXV) endemic country. Seventy-nine cases with information were male and 66 reported being gay, bisexual, or other men who have sex with men. This is the first reported sustained MPXV transmission in the UK, with human-to-human transmission through close contacts, including in sexual networks. Improving case ascertainment and onward-transmission preventive measures are ongoing.

BackgroundThis study aimed to identify and resolve discordant variant interpretations across clinical molecular genetic laboratories through the Canadian Open Genetics Repository (COGR), an online collaborative effort for variant sharing and interpretation.MethodsLaboratories uploaded variant data to the Franklin Genoox platform. Reports were issued to each laboratory, summarising variants where conflicting classifications with another laboratory were noted. Laboratories could then reassess variants to resolve discordances. Discordance was calculated using a five-tier model (pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), benign (B)), a three-tier model (LP/P are positive, VUS are inconclusive, LB/B are negative) and a two-tier model (LP/P are clinically actionable, VUS/LB/B are not). We compared the COGR classifications to automated classifications generated by Franklin.ResultsTwelve laboratories submitted classifications for 44 510 unique variants. 2419 variants (5.4%) were classified by two or more laboratories. From baseline to after reassessment, the number of discordant variants decreased from 833 (34.4% of variants reported by two or more laboratories) to 723 (29.9%) based on the five-tier model, 403 (16.7%) to 279 (11.5%) based on the three-tier model and 77 (3.2%) to 37 (1.5%) based on the two-tier model. Compared with the COGR classification, the automated Franklin classifications had 94.5% sensitivity and 96.6% specificity for identifying actionable (P or LP) variants.ConclusionsThe COGR provides a standardised mechanism for laboratories to identify discordant variant interpretations and reduce discordance in genetic test result delivery. Such quality assurance programmes are important as genetic testing is implemented more widely in clinical care.

Two of the four human ubiquitin-encoding genes express ubiquitin as an N-terminal fusion precursor polypeptide, with either ribosomal protein (RP) RPS27a or RPL40 at the C-terminus. RPS27a and RPL40 have been proposed to be important for the induction of the tumour suppressor p53 in response to defects in ribosome biogenesis, suggesting that they may play a role in the coordination of ribosome production, ubiquitin levels and p53 signalling. Here, we report that RPS27a is cleaved from the ubiquitin-RP precursor in a process that appears independent of ribosome biogenesis. In contrast to other RPs, the knockdown of either RPS27a or RPL40 did not stabilise the tumour suppressor p53 in U2OS cells. Knockdown of neither protein blocked p53 stabilisation following inhibition of ribosome biogenesis by actinomycin D, indicating that they are not needed for p53 signalling in these cells. However, the knockdown of both RPS27a and RPL40 in MCF7 and LNCaP cells robustly induced p53, consistent with observations made with the majority of other RPs. Importantly, RPS27a and RPL40 are needed for rRNA production in all cell lines tested. Our data suggest that the role of RPS27a and RPL40 in p53 signalling, but not their importance in ribosome biogenesis, differs between cell types.

The nucleolar surveillance pathway monitors nucleolar integrity and responds to nucleolar stress by mediating binding of ribosomal proteins to MDM2, resulting in p53 accumulation. Inappropriate pathway activation is implicated in the pathogenesis of ribosomopathies, while drugs selectively activating the pathway are in trials for cancer. Despite this, the molecular mechanism(s) regulating this process are poorly understood. Using genome-wide loss-of-function screens, we demonstrate the ribosome biogenesis axis as the most potent class of genes whose disruption stabilizes p53. Mechanistically, we identify genes critical for regulation of this pathway, including HEATR3. By selectively disabling the nucleolar surveillance pathway, we demonstrate that it is essential for the ability of all nuclear-acting stresses, including DNA damage, to induce p53 accumulation. Our data support a paradigm whereby the nucleolar surveillance pathway is the central integrator of stresses that regulate nuclear p53 abundance, ensuring that ribosome biogenesis is hardwired to cellular proliferative capacity.

In this paper, we develop a robust economic model predictive controller for the containment of stochastic Susceptible-Exposed-Infected-Vigilant (SEIV) epidemic processes which drives the process to extinction quickly, while minimizing the rate at which control resources are used. The work we present here is significant in that it addresses the problem of efficiently controlling general stochastic epidemic systems without relying on mean-field approximation, which is an important issue in the theory of stochastic epidemic processes. This enables us to provide rigorous convergence guarantees on the stochastic epidemic model itself, improving over the mean-field type convergence results of most prior work. There are two primary technical difficulties addressed in treating this problem: (i) constructing a means of tractably approximating the evolution of the process, so that the designed approximation is robust to the modeling error introduced by the applied moment closure, and (ii) guaranteeing that the designed controller causes the closed-loop system to drive the SEIV process to extinction quickly. As an application, we use the developed framework for optimizing the use of quarantines in containing an SEIV epidemic outbreak., Comment: 16 pages, 3 figures; Revision to correct minor typos and clarify some notation

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Proteins are the effector molecules of biology and are the target of most drugs. To identify proteins and related pathways that may play a causal role in stroke pathogenesis, we used Mendelian randomisation (MR). We tested potential causal effects of 308 plasma proteins (measured in 4,994 blood donors from the INTERVAL study) on stroke outcomes (derived from the MEGASTROKE GWAS) in a two-sample MR framework and assessed whether these associations could be mediated by cardiovascular risk factors. We extended the analysis to identify whether pharmacological targeting of these proteins might have potential adverse side-effects or beneficial effects for other conditions through Phenome-wide MR (Phe-MR) in UK Biobank. MR showed an association between stroke and genetically predicted plasma levels of TFPI, IL6RA, MMP12, CD40, TMPRSS5 and CD6 (P≤1.62⋅10−4). We identified six risk factors (atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes) that were associated with stroke (P≤0.0071) using MR. The association of TFPI, IL6RA and TMPRSS5 with stroke could be mediated by these risk factors, such as body mass index, white matter hyperintensity and atrial fibrillation. Thirty-six additional proteins were potentially causal for one or more of these risk factors. The Phe-MR suggested that targeting TFPI could have potential beneficial effects on other disorders of arteries and hyperlipidaemia in addition to stroke. Our results highlight novel causal pathways and potential therapeutic targets for stroke.

Cardiometabolic diseases are frequently polygenic in architecture, comprising a large number of risk alleles with small effects spread across the genome1–3. Polygenic scores (PGS) aggregate these into a metric representing an individual’s genetic predisposition to disease. PGS have shown promise for early risk prediction4–7 and there is an open question as to whether PGS can also be used to understand disease biology8. Here, we demonstrate that cardiometabolic disease PGS can be used to elucidate the proteins underlying disease pathogenesis. In 3,087 healthy individuals, we found that PGS for coronary artery disease, type 2 diabetes, chronic kidney disease and ischaemic stroke are associated with the levels of 49 plasma proteins. Associations were polygenic in architecture, largely independent of cis and trans protein quantitative trait loci and present for proteins without quantitative trait loci. Over a follow-up of 7.7 years, 28 of these proteins associated with future myocardial infarction or type 2 diabetes events, 16 of which were mediators between polygenic risk and incident disease. Twelve of these were druggable targets with therapeutic potential. Our results demonstrate the potential for PGS to uncover causal disease biology and targets with therapeutic potential, including those that may be missed by approaches utilizing information at a single locus., Ritchie et al. use polygenic scores to identify plasma proteins with causal roles in cardiometabolic disease.

Proteins are the effector molecules of biology and are the target of most drugs. To identify proteins and related pathways that may play a causal role in stroke pathogenesis, we used Mendelian randomisation (MR). We tested potential causal effects of 308 plasma proteins (measured in 4,994 blood donors from the INTERVAL study) on stroke outcomes (derived from the MEGASTROKE GWAS) in a two-sample MR framework and assessed whether these associations could be mediated by cardiovascular risk factors. We extended the analysis to identify whether pharmacological targeting of these proteins might have potential adverse side-effects or beneficial effects for other conditions through Phenome-wide MR (Phe-MR) in UK Biobank.MR showed an association between stroke and genetically predicted plasma levels of TFPI, IL6RA, MMP12, CD40, TMPRSS5 and CD6 (P≤1.62×10−4). We identified six risk factors (atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes) that were associated with stroke (P≤0.0071) using MR. The association of TFPI, IL6RA and TMPRSS5 with stroke could be mediated by these risk factors, such as body mass index, white matter hyperintensity and atrial fibrillation. Thirty-six additional proteins were potentially causal for one or more of these risk factors. The Phe-MR suggested that targeting TFPI could have potential beneficial effects on other disorders of arteries and hyperlipidaemia in addition to stroke. Our results highlight novel causal pathways and potential therapeutic targets for stroke.

Synthesis of eukaryotic ribosomes involves the assembly and maturation of precursor particles (pre-ribosomal particles) containing ribosomal RNA (rRNA) precursors, ribosomal proteins (RPs) and a plethora of assembly factors (AFs). Formation of the earliest precursors of the 60S ribosomal subunit (pre-60S r-particle) is among the least understood stages of ribosome biogenesis. It involves the Npa1 complex, a protein module suggested to play a key role in the early structuring of the pre-rRNA. Npa1 displays genetic interactions with the DExD-box protein Dbp7 and interacts physically with the snR190 box C/D snoRNA. We show here that snR190 functions as a snoRNA chaperone, which likely cooperates with the Npa1 complex to initiate compaction of the pre-rRNA in early pre-60S r-particles. We further show that Dbp7 regulates the dynamic base-pairing between snR190 and the pre-rRNA within the earliest pre-60S r-particles, thereby participating in structuring the peptidyl transferase center (PTC) of the large ribosomal subunit., The Henry/Henras group is supported by grants from ANR (ANR-20-CE12-0026) and funding from CNRS and University of Toulouse. R.A.M. is supported by grants from the Rectorat of Lebanese University. M.J. is supported by a Ph.D. fellowship from the Lebanese University and CIOES Organization. The group of J.d.l.C. is supported by the Spanish Ministry of Science and Innovation [PID2019-103859-GB-I00 AEI/ 10.13039/501100011033], and the Andalusian Regional Government (JA; BIO-271). J.C. was supported by a Ph.D. fellowship (PIF) from the University of Seville, and S.M.-V. is an academic research staff of the JA (PAIDI2020). M.T.B. and K.E.B. are supported by funding from the Deutsche Forschungsgemeinschaft (SFB860) and the University Medical Centre Göttingen.

Altered expression of box C/D small nucleolar RNAs (snoRNAs) is implicated in human diseases, including cancer. Box C/D snoRNAs canonically direct site-specific, 2’-O-methylation but the extent to which they participate in other functions remains unclear. To identify RNA targets of box C/D snoRNAs in human cells, we applied two techniques based on UV crosslinking, proximity ligation and sequencing of RNA hybrids (CLASH and FLASH). These identified hundreds of novel snoRNA interactions with rRNA, snoRNAs and mRNAs. We developed an informatic pipeline to rigorously call interactions predicted to direct methylation. Multiple snoRNA-rRNA interactions identified were not predicted to direct RNA methylation. These potentially modulate methylation efficiency and/or contribute to folding dynamics. snoRNA-mRNA hybrids included 1,300 interactions between 117 snoRNA families and 940 mRNAs. Human U3 is substantially more abundant than other snoRNAs and represented about 50% of snoRNA-mRNA hybrids. The distribution of U3 interactions across mRNAs also differed from other snoRNAs. Following U3 depletion, mRNAs showing altered abundance were strongly enriched for U3 CLASH targets. Most human snoRNAs are excised from pre-mRNA introns. Enrichment for snoRNA association with branch point regions of introns that contain snoRNA genes was common, suggesting widespread regulation of snoRNA maturation.

I survey and illustrate the main time series models that Mandelbrot introduced into time series analysis in the 1960s and 1970s. I focus particularly on the members of the additive fractional stable family including Lévy flights and fractional Brownian motion (fBm), noting some of the less well‐known aspects of this family, such as the cases when the self‐similarity exponent H and the Hurst exponent J differ. I briefly discuss the role of multiplicative models in modeling the physics of cascades. I then recount the still little‐known story of Mandelbrot's work on fractional renewal models in the late 1960s, explaining how these differ from their more familiar fBm counterpart and form a “missing link” between fBm and the problem of random change points. I conclude by highlighting the frontier problem of damped fractional models.\ud \ud

To report BRCA1 and BRCA2 (BRCA1/2) variant reassessments and reclassifications between 2012 and 2017 at the Advanced Molecular Diagnostics Laboratory (AMDL) in Toronto, Canada, which provides BRCA1/2 testing for patients in Ontario, and to compare AMDL variant classifications with submissions in ClinVar. Variants were assessed using a standardized variant assessment tool based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology’s guidelines and tracked in an in-house database. Variants were shared through the Canadian Open Genetics Repository and submitted to ClinVar for comparison against other laboratories. AMDL identified 1209 BRCA1/2 variants between 2012 and 2017. During this period, 32.9% (398/1209) of variants were reassessed and 12.4% (150/1209) were reclassified. The majority of reclassified variants were downgraded (112/150, 74.7%). Of the reclassified variants, 63.3% (95/150) were reclassified to benign, 20.7% (31/150) to likely benign, 10.0% (15/150) to variant of uncertain significance, 2.0% (3/150) to likely pathogenic, and 4.0% (6/150) to pathogenic. Discordant ClinVar submissions were found for 40.4% (488/1209) of variants. BRCA1/2 variants may be reclassified over time. Reclassification presents ethical and practical challenges related to recontacting patients. Data sharing is essential to improve variant interpretation, to help patients receive appropriate care based on their genetic results.

The microstructure–property relationship of a pure tin part built using the drop-on-demand technique of liquid metal jetting, a cost–effective alternative to selective laser-melting or sintering techniques, was determined. The microstructure of the as-built tin is observed to have minimal stored strain, low dislocation density, few to no voids, and the presence of only the β-tin phase; concurrently, mechanical properties are shown to be identical to the traditionally manufactured tin.

The frequency and severity of heatwaves is expected to increase as the global climate warms. We apply crossing theory for the first time to determine heatwave properties solely from the distribution of daily observations without time-correlation information. We use Central England Temperature time series to quantify how the simple increased occurrence of higher temperatures makes heatwaves (consecutive summer days with temperatures exceeding a threshold) more frequent and intense. We find an overall twofold to threefold increase in heatwave activity since the late 1800's. Week-long heatwaves that on average return every 5 years were typically below ∼28 ◦C and now typically exceed it. Our analysis takes as inputs average user-specific heat wave properties. Its output pinpoints the range of temperatures for which changes in the distribution must be well resolved statistically in order to track how these heatwave properties are changing. This provides a quantitative benchmark for models used for the attribution of heat waves.

A higher body mass index (BMI) is a recognised risk factor for thrombosis. Platelets are essential for haemostasis but also contribute to thrombosis when activated pathologically. We hypothesised that an increase in BMI may lead to changes in platelet characteristics, thereby contributing to increased thrombotic risk.The effect of BMI on platelet traits measured by Sysmex XN-1000 was explored in 33388 UK blood donors from the INTERVAL study. Linear regression was used for observational analyses between BMI and platelet characteristics. Mendelian randomization (MR) was used to estimate a causal effect with BMI proxied by a genetic risk score. Follow-up analysis explored the relevance of platelet characteristics on whole blood platelet aggregation in a pre-operative cardiac cohort (COPTIC) using linear regression.Observationally, higher BMI was positively associated with greater plateletcrit (PCT), platelet count (PLT), immature platelet count (IPC) and side fluorescence (SFL, a measure of mRNA content used to derive IPC). MR provided causal estimates for a positive effect of BMI on both SFL and IPC (IPC 0.06 SDs higher per SD higher BMI, 95% CI 0.006 to 0.12, P=0.03), but there was no strong evidence for a causal effect of BMI on PCT or PLT. The COPTIC study provided observational evidence for a positive association between IPC and whole blood platelet aggregation induced by adrenaline, TRAP-6 and ADP. Our results indicate that higher BMI raises the number of immature platelets, which is associated with greater whole blood platelet aggregation. Higher IPC could therefore contribute to obesity-related thrombosis.EssentialsA higher body mass index (BMI) is associated with thrombotic disorders.We explored whether BMI is associated with platelets traits, key cells involved in thrombosis.We found causal evidence for higher BMI raising immature platelet count (IPC).Higher IPC is associated with enhanced platelet aggregation in a cardiac surgery cohort.

RNA helicases play important roles in diverse aspects of RNA metabolism through their functions in remodelling ribonucleoprotein complexes (RNPs), such as pre-ribosomes. Here, we show that the DEAD box helicase Dbp3 is required for efficient processing of the U18 and U24 intron-encoded snoRNAs and 2′-O-methylation of various sites within the 25S ribosomal RNA (rRNA) sequence. Furthermore, numerous box C/D snoRNPs accumulate on pre-ribosomes in the absence of Dbp3. Many snoRNAs guiding Dbp3-dependent rRNA modifications have overlapping pre-rRNA basepairing sites and therefore form mutually exclusive interactions with pre-ribosomes. Analysis of the distribution of these snoRNAs between pre-ribosome-associated and ‘free’ pools demonstrated that many are almost exclusively associated with pre-ribosomal complexes. Our data suggest that retention of such snoRNPs on pre-ribosomes when Dbp3 is lacking may impede rRNA 2′-O-methylation by reducing the recycling efficiency of snoRNPs and by inhibiting snoRNP access to proximal target sites. The observation of substoichiometric rRNA modification at adjacent sites suggests that the snoRNPs guiding such modifications likely interact stochastically rather than hierarchically with their pre-rRNA target sites. Together, our data provide new insights into the dynamics of snoRNPs on pre-ribosomal complexes and the remodelling events occurring during the early stages of ribosome assembly.

Background Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins. Methods We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI. Results Observationally, BMI was associated with 1576 proteins (P −5), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48–0.79, P = 1.6 × 10−15), FABP4 (0.64 SD per SD BMI, 95% CI 0.46–0.83, P = 6.7 × 10−12) and SHBG (−0.45 SD per SD BMI, 95% CI −0.65 to −0.25, P = 1.4 × 10−5). There was agreement in the magnitude of observational and MR estimates (R2 = 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease. Conclusions This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease.

The nucleolar surveillance pathway (NSP) monitors nucleolar fidelity and responds to nucleolar stresses (i.e., inactivation of ribosome biogenesis) by mediating the inhibitory binding of ribosomal proteins (RPs) to mouse double minute 2 homolog (MDM2), a nuclear-localised E3 ubiquitin ligase, which results in p53 accumulation. Inappropriate activation of the NSP has been implicated in the pathogenesis of collection of human diseases termed “ribosomopathies”, while drugs that selectively activate the NSP are now in trials for cancer. Despite the clinical significance, the precise molecular mechanism(s) regulating the NSP remain poorly understood. Using genome-wide loss of function screens, we demonstrate the ribosome biogenesis (RiBi) axis as the most potent class of genes whose disruption stabilises p53. Furthermore, we identified a novel suite of genes critical for the NSP, including a novel mammalian protein implicated in 5S ribonucleoprotein particle (5S-RNP) biogenesis, HEATR3. By selectively disabling the NSP, we unexpectedly demonstrate that a functional NSP is required for the ability of all nuclear acting stresses tested, including DNA damage, to robustly induce p53 accumulation. Together, our data demonstrates that the NSP has evolved as the dominant central integrator of stresses that regulate nuclear p53 abundance, thus ensuring RiBi is hardwired to cellular proliferative capacity.

Introduction: The lack of approved specific therapeutic agents to treat coronavirus disease (COVID‐19) associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has led to the rapid implementation of convalescent plasma therapy (CPT) trials in many countries, including the United Kingdom. Effective CPT is likely to require high titres of neutralising antibody (nAb) in convalescent donations. Understanding the relationship between functional neutralising antibodies and antibody levels to specific SARS‐CoV‐2 proteins in scalable assays will be crucial for the success of a large‐scale collection. We assessed whether neutralising antibody titres correlated with reactivity in a range of enzyme‐linked immunosorbent assays (ELISA) targeting the spike (S) protein, the main target for human immune response. Methods: Blood samples were collected from 52 individuals with a previous laboratory‐confirmed SARS‐CoV‐2 infection. These were assayed for SARS‐CoV‐2 nAbs by microneutralisation and pseudo‐type assays and for antibodies by four different ELISAs. Receiver operating characteristic (ROC) analysis was used to further identify sensitivity and specificity of selected assays to identify samples containing high nAb levels. Results: All samples contained SARS‐CoV‐2 antibodies, whereas neutralising antibody titres of greater than 1:20 were detected in 43 samples (83% of those tested) and >1:100 in 22 samples (42%). The best correlations were observed with EUROimmun immunoglobulin G (IgG) reactivity (Spearman Rho correlation coefficient 0.88; p 1:100 with 100% specificity using a reactivity index of 9.1 (13/22). Discussion: Robust associations between nAb titres and reactivity in several ELISA‐based antibody tests demonstrate their possible utility for scaled‐up production of convalescent plasma containing potentially therapeutic levels of anti‐SARS‐CoV‐2 nAbs.

Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models.

47 p.-11 fig., Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis., This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the Department of Health and Social Care (England), the Chief Scientist Office of the Scottish Government Health and Social Care Directorates, the Health and Social Care Research and Development Division (Welsh Government), the Public Health Agency (Northern Ireland), the British Heart Foundation and Wellcome. N.C. is supported by an EBI–Sanger Postdoctoral Fellowship. A.G.-D. receives funding from the NIHR Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust. E.Y.-D. was funded by the Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research Grants Scheme. J.M.M.H. was funded by the NIHR Cambridge BRC (BRC-1215-20014)*. P.F.C.is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Evelyn Trust and the NIHR Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. C.H.W.-G. is supported by a RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1) and by the Cambridge Centre for Parkinson-Plus. N.S. is supported by the Wellcome Trust(grant number 098051 until 30 September 2016 and 206194 from 1 October 2016),the Cambridge BHF Centre of Research Excellence (RE/18/1/34212) and the NIHR Cambridge Biomedical Research Centre Biomedical Resources Grant, University of Cambridge, Cardiovascular Theme (RG64226). J.D. holds a British Heart Foundation Professorship and an NIHR Senior Investigator Award*. R.A.L. is supported by grants from Parkinson’s UK. Sequencing of INTERVAL samples was supported by the Wellcome Trust (grant number 206194). Metabolon metabolomics assays were funded by the NIHR BioResource, the Wellcome Trust (grant number 206194) and the NIHR Cambridge BRC (BRC-1215-20014)*. Nightingale Health NMR assays were funded by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). SomaLogic assays were funded by Merck and the NIHR Cambridge BRC (BRC-1215-20014)*. ICICLE-PD was funded by Parkinson’s UK (J-0802, G-1301, G-1507) and the Lockhart Parkinson’s Disease Research Fund and supported by the NIHR Newcastle Biomedical Research Unit and the NIHR Cambridge Biomedical Research Centre (146281). The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). Genetic work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372.

Background Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. Methods A cross-sectional study of 993 plasma proteins among 2,882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified trans-ethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR . Results Fifty-seven plasma proteins were associated with eGFR, including one novel protein. Twenty-three of these were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. Conclusions In a discovery-replication setting, we identified 57 proteins trans-ethnically associated with eGFR. The revealed causal relationships are an important stepping-stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.

Serological reactivity was analysed in plasma from 436 individuals with a history of disease compatible with COVID-19, including 256 who had been laboratory-confirmed with SARS-CoV-2 infection. Over 99% of laboratory-confirmed cases developed a measurable antibody response (254/256) and 88% harboured neutralising antibodies (226/256). Antibody levels declined over 3 months following diagnosis, emphasising the importance of the timing of convalescent plasma collections. Binding antibody measurements can inform selection of convalescent plasma donors with high neutralising antibody levels.

BACKGROUND: Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins. METHODS: We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI. RESULTS: Observationally, BMI was associated with 1576 proteins (P < 1.4 × 10-5), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48-0.79, P = 1.6 × 10-15), FABP4 (0.64 SD per SD BMI, 95% CI 0.46-0.83, P = 6.7 × 10-12) and SHBG (-0.45 SD per SD BMI, 95% CI -0.65 to -0.25, P = 1.4 × 10-5). There was agreement in the magnitude of observational and MR estimates (R2 = 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease. CONCLUSIONS: This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease.

Introduction. The lack of approved specific therapeutic agents to treat COVID-19 associated with SARS coronavirus 2 (SARS-CoV-2) infection has led to the rapid implementation and/or randomised controlled trials of convalescent plasma therapy (CPT) in many countries including the UK. Effective CPT is likely to require high titres of neutralising antibody levels in convalescent donations. Understanding the relationship between functional neutralising antibodies and antibody levels to specific SARS-CoV-2 proteins in scalable assays will be crucial for the success of large-scale collection and use of convalescent plasma. We assessed whether neutralising antibody titres correlated with reactivity in a range of ELISA assays targeting the spike (S) protein, the main target for human immune response. Methods. Blood samples were collected from 52 individuals with a previous laboratory confirmed SARS-CoV-2 infection at least 28 days after symptom resolution. These were assayed for SARS-CoV-2 neutralising antibodies by microneutralisation and pseudotype assays, and for antibodies by four different ELISAs. ROC analysis was used to further identify sensitivity and specificity of selected assays to identify samples containing high neutralising antibody levels suitable for clinical use of convalescent plasma. Results. All samples contained SARS-CoV-2 antibodies, whereas neutralising antibody titres of greater than 1:20 were detected in 43 samples (83% of those tested) and >1:100 in 22 samples (42%). The best correlations were observed with EUROimmun IgG ELISA S/CO reactivity (Spearman Rho correlation co-efficient 0.88; p1:100 with 100% specificity using a reactivity index of 9.1 (13/22). Discussion. Robust associations between virus neutralising antibody titres and reactivity in several ELISA-based antibody tests demonstrate their possible utility for scaled-up production of convalescent plasma containing potentially therapeutic levels of anti-SARS-CoV-2 neutralising antibodies.

Additive manufacturing systems are becoming progressively more capable of printing geometrically complex structures from a wide range of materials. To ensure the print quality of these materials over the duration of the build process, there is a need for in-situ diagnostics which can provide real-time information during fabrication, as well as information that can be processed after print completion. Here we present an in-situ radio frequency diagnostic for liquid metal jetting, which employs a millimeter-wave waveguide device to monitor the impedance changes caused by moving droplets. Experimental results indicate promise for the characterization of size, timing, and motion of metal droplets in an advanced manufacturing system.

BackgroundThe COVID-19 pandemic caused >1 million infections during January-March 2020. There is an urgent need for reliable antibody detection approaches to support diagnosis, vaccine development, safe release of individuals from quarantine, and population lock-down exit strategies. We set out to evaluate the performance of ELISA and lateral flow immunoassay (LFIA) devices.MethodsWe tested plasma for COVID (SARS-CoV-2) IgM and IgG antibodies by ELISA and using nine different LFIA devices. We used a panel of plasma samples from individuals who have had confirmed COVID infection based on a PCR result (n=40), and pre-pandemic negative control samples banked in the UK prior to December-2019 (n=142).ResultsELISA detected IgM or IgG in 34/40 individuals with a confirmed history of COVID infection (sensitivity 85%, 95%CI 70-94%), vs. 0/50 pre-pandemic controls (specificity 100% [95%CI 93-100%]). IgG levels were detected in 31/31 COVID-positive individuals tested ≥10 days after symptom onset (sensitivity 100%, 95%CI 89-100%). IgG titres rose during the 3 weeks post symptom onset and began to fall by 8 weeks, but remained above the detection threshold. Point estimates for the sensitivity of LFIA devices ranged from 55-70% versus RT-PCR and 65-85% versus ELISA, with specificity 95-100% and 93-100% respectively. Within the limits of the study size, the performance of most LFIA devices was similar.ConclusionsCurrently available commercial LFIA devices do not perform sufficiently well for individual patient applications. However, ELISA can be calibrated to be specific for detecting and quantifying SARS-CoV-2 IgM and IgG and is highly sensitive for IgG from 10 days following first symptoms.

ObjectivesTo use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels.DesignTwo-sample Mendelian randomization (MR) analysis.SettingSummary-level genetic association data.ParticipantsParticipants were predominantly of European ancestry. Variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors (body mass index, chronic obstructive pulmonary disease, lifetime smoking index, low-density lipoprotein cholesterol, systolic blood pressure and type 2 diabetes mellitus) were selected from publicly available genome-wide association study data (sample sizes ranging from 188,577 to 898,130 participants). Genetic association estimates for lung expression of ACE2 and TMPRSS2 were obtained from the Gene-Tissue Expression (GTEx) project (515 participants) and the Lung eQTL Consortium (1,038 participants). Genetic association estimates for circulating plasma ACE2 levels were obtained from the INTERVAL study (4,947 participants).Main outcomes and measuresLung ACE2 and TMPRSS2 expression and plasma ACE2 levels.ResultsThere were no association of genetically proxied ACE inhibition with any of the outcomes considered here. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in GTEx (p = 4×10−4) and with circulating plasma ACE2 levels in INTERVAL (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations between genetically predicted levels of the other cardiometabolic traits with the outcomes.ConclusionsThis study does not provide evidence to support that ACE inhibitor antihypertensive drugs affect lung ACE2 and TMPRSS2 expression or plasma ACE2 levels. In the current COVID-19 pandemic, our findings do not support a change in ACE inhibitor medication use without clinical justification.Summary boxesWhat is already known on this topicSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic.Serine protease TMPRSS2 is involved in priming the SARS-CoV-2 spike protein for cellular entry through the angiotensin-converting enzyme 2 (ACE2) receptor.Expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for risk of SARS-CoV-2 infection and severity of COVID-19.What this study addsWe used human genetic variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 expression and circulating ACE2 levels.Our findings do not support the hypothesis that ACE inhibitors have effects on ACE2 expression.We found some support for an association of genetic liability to type 2 diabetes mellitus with higher lung ACE2 expression and plasma ACE2 levels, but evidence was inconsistent across studies.

Recent research has demonstrated the existence of a new type of solar event, the "terminator." Unlike the Sun's signature events, flares and Coronal Mass Ejections, the terminator most likely originates in the solar interior, at or near the tachocline. The terminator signals the end of a magnetic activity cycle at the Sun's equator and the start of a sunspot cycle at mid latitudes. Observations indicate that the time difference between these events is very short, less than a solar rotation, in the context of the sunspot cycle. As the (definitive) start and end point of solar activity cycles the precise timing of terminators should permit new investigations into the meteorology of our star's atmosphere. In this letter we use a standard method in signal processing, the Hilbert transform, to identify a mathematically robust signature of terminators in sunspot records and in radiative proxies. Using a linear extrapolation of the Hilbert phase of the sunspot number and F10.7 solar radio flux time series we can achieve higher fidelity historical terminator timing than previous estimates have permitted. Further, this method presents a unique opportunity to project, from analysis of sunspot data, when the next terminator will occur, May 2020 ($+4$, $-1.5$ months), and trigger the growth of sunspot cycle 25., 18 pages, 6 figures, 1 table. Final (minor corrections) revision as submitted to Solar Physics, January 2020

BackgroundExome and genome sequencing have been demonstrated to increase diagnostic yield in paediatric populations, improving treatment options and providing risk information for relatives. There are limited studies examining the clinical utility of these tests in adults, who currently have limited access to this technology.MethodsPatients from adult and cancer genetics clinics across Toronto, Ontario, Canada were recruited into a prospective cohort study evaluating the diagnostic utility of exome and genome sequencing in adults. Eligible patients were ≥18 years of age and suspected of having a hereditary disorder but had received previous uninformative genetic test results. In total, we examined the diagnostic utility of exome and genome sequencing in 47 probands and 34 of their relatives who consented to participate and underwent exome or genome sequencing.ResultsOverall, 17% (8/47) of probands had a pathogenic or likely pathogenic variant identified in a gene associated with their primary indication for testing. The diagnostic yield for patients with a cancer history was similar to the yield for patients with a non-cancer history (4/18 (22%) vs 4/29 (14%)). An additional 24 probands (51%) had an inconclusive result. Secondary findings were identified in 10 patients (21%); three had medically actionable results.ConclusionsThis study lends evidence to the diagnostic utility of exome or genome sequencing in an undiagnosed adult population. The significant increase in diagnostic yield warrants the use of this technology. The identification and communication of secondary findings may provide added value when using this testing modality as a first-line test.

Geomagnetic indices are routinely used to characterize space weather event intensity. The DST index is well resolved, but is only available over 5 solar cycles. The aa index extends over 14 cycles but is highly discretized with poorly resolved extremes. We parameterize extreme aa activity by the annual averaged top few % of observed values, show these are exponentially distributed and they track annual DST index minima. This gives a 14 cycle average of ~ 4% chance of at least one great (DST nT) storm and ~ 28% chance of at least one severe (DST nT) storm per year. At least one DST=‐809 [‐663,‐955] nT event in a given year would be a 1:151 year event. Carrington event estimate DST ~ ‐850 nT is within the same distribution as other extreme activity seen in aa since 1868 so that its likelihood can be deduced from that of more moderate events. Events with DST ≲ ‐1000 nT are in a distinct class, requiring special conditions.

SummaryBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.

SUMMARYThousands of genetic associations with phenotypes of blood cells are known, but few are with phenotypes relevant to cell function. We performed GWAS of 63 flow-cytometry phenotypes, including measures of cell granularity, nucleic acid content, and reactivity, in 39,656 participants in the INTERVAL study, identifying 2,172 variant-trait associations. These include associations mediated by functional cellular structures such as secretory granules, implicated in vascular, thrombotic, inflammatory and neoplastic diseases. By integrating our results with epigenetic data and with signals from molecular abundance/disease GWAS, we infer the hematopoietic origins of population phenotypic variation and identify the transcription factor FOG2 as a regulator of plateletα-granularity. We show how flow cytometry genetics can suggest cell types mediating complex disease risk and suggest efficacious drug targets, presenting Daclizumab/Vedolizumab in autoimmune disease as positive controls. Finally, we add to existing evidence supporting IL7/IL7-R as drug targets for multiple sclerosis.

SUMMARYMost loci identified by GWAS have been found in populations of European ancestry (EA). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EA individuals, we identified 5,552 trait-variant associations at P−9, including 71 novel loci not found in EA populations. We also identified novel ancestry-specific variants not found in EA, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional, and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EA-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations, and compared genetic architecture and the impact of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non–self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.

One of the most intriguing facets of the climate system is that it exhibits variability across all temporal and spatial scales; pronounced examples are temperature and precipitation. The structure of this variability, however, is not arbitrary. Over certain spatial and temporal ranges, it can be described by scaling relationships in the form of power laws in probability density distributions and autocorrelation functions. These scaling relationships can be quantified by scaling exponents which measure how the variability changes across scales and how the intensity changes with frequency of occurrence. Scaling determines the relative magnitudes and persistence of natural climate fluctuations. Here, we review various scaling mechanisms and their relevance for the climate system. We show observational evidence of scaling and discuss the application of scaling properties and methods in trend detection, climate sensitivity analyses, and climate prediction.

Summary Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation., Graphical Abstract, Highlights • Largest genome-wide association study of blood cell traits to date • Empiric assessments of omnigenic and infinitesimal models of polygenic variation • Functional insights into how genetic variants impact human hematopoiesis • Assessment of the effect of polygenic trait scores upon blood diseases, Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases.