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Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies. Godkänd;2023;Nivå 0;2023-04-06 (hanlid);Funder: for more funders see the article https://doi.org/10.1038/s41467-023-36862-w

Plant productivity varies due to environmental heterogeneity, and theory suggests that plant diversity can reduce this variation. While there is strong evidence of diversity effects on temporal variability of productivity, whether this mechanism extends to variability across space remains elusive. Here we determine the relationship between plant diversity and spatial variability of productivity in 83 grasslands, and quantify the effect of experimentally increased spatial heterogeneity in environmental conditions on this relationship. We found that communities with higher plant species richness (alpha and gamma diversity) have lower spatial variability of productivity as reduced abundance of some species can be compensated for by increased abundance of other species. In contrast, high species dissimilarity among local communities (beta diversity) is positively associated with spatial variability of productivity, suggesting that changes in species composition can scale up to affect productivity. Experimentally increased spatial environmental heterogeneity weakens the effect of plant alpha and gamma diversity, and reveals that beta diversity can simultaneously decrease and increase spatial variability of productivity. Our findings unveil the generality of the diversity-stability theory across space, and suggest that reduced local diversity and biotic homogenization can affect the spatial reliability of key ecosystem functions.

Availability of light and CO2, substrates of microalgae photosynthesis, is frequently far from optimal. Microalgae activate photoprotection under strong light, to prevent oxidative damage, and the CO2 Concentrating Mechanism (CCM) under low CO2, to raise intracellular CO2 levels. The two processes are interconnected; yet, the underlying transcriptional regulators remain largely unknown. Employing a large transcriptomic data compendium of Chlamydomonas reinhardtii’s responses to different light and carbon supply, we reconstruct a consensus genome-scale gene regulatory network from complementary inference approaches and use it to elucidate transcriptional regulators of photoprotection. We show that the CCM regulator LCR1 also controls photoprotection, and that QER7, a Squamosa Binding Protein, suppresses photoprotection- and CCM-gene expression under the control of the blue light photoreceptor Phototropin. By demonstrating the existence of regulatory hubs that channel light- and CO2-mediated signals into a common response, our study provides an accessible resource to dissect gene expression regulation in this microalga.

Fast, efficient information transfer is essential for the brain to ensure survival. As recently shown in functional magnetic resonance imaging with high spatial resolution, turbulence appears to offer a fundamental way to facilitate energy and information transfer across spatiotemporal scales in brain dynamics. However, given that this imaging modality is comparably slow and not directly linked with neuronal activity, here we investigated the existence of turbulence in fast whole-brain neural dynamics measured with magnetoencephalography (MEG). The coarse spatial observations in MEG necessitated that we created and validated a empirical measure of turbulence. We found that the measure of edge-centric metastability perfectly detected turbulence in a ring of non-local coupled oscillators where the ground-truth was analytically known, even at a coarse spatial scale of observations. This allowed us to use this measure in the spatially coarse, empirical large-scale MEG data from 89 human participants. We demonstrated turbulence in fast neuronal dynamics and used this to quantify information transfer in the brain. The results demonstrate that the necessary efficiency of brain function is dependent on an underlying turbulent regime. G.D. is supported by the Human Brain Project Specific Grant Agreement 3 Grant agreement no. 945539 and by the Spanish Research Project AWAKENING: using whole-brain models perturbational approaches for predicting external stimulation to force transitions between different brain states, ref. PID2019-105772GB-I00/AEI/10.13039/501100011033, financed by the Spanish Ministry of Science, Innovation and Universities (MCIU), State Research Agency (AEI). Y.S.P is supported by European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant 896354. M.L.K. is supported by the Centre for Eudaimonia and Human Flourishing (funded by the Pettit and Carlsberg Foundations) and Center for Music in the Brain (funded by the Danish National Research Foundation, DNRF117).

The wiring of the brain connects micro-architecturally diverse neuronal populations. The conventional graph model encodes macroscale brain connectivity as a network of nodes and edges, but abstracts away the rich biological detail of each regional node. Regions are different in terms of their microscale attributes, many of which are readily available through modern technological advances and data-sharing initiatives. How is macroscale connectivity related to nodal attributes? Here we investigate the systematic arrangement of white-matter connectivity with respect to multiple biological annotations. Namely, we formally study assortative mixing in annotated connectomes by quantifying the tendency for regions to be connected with each other based on the similarity of their micro-architectural attributes. We perform all experiments using four cortico-cortical connectome datasets from three different species (human, macaque and mouse), and consider a range of molecular, cellular and laminar annotations, including gene expression, neurotransmitter receptors, neuron density, laminar thickness and intracortical myelin. Importantly, we disentangle the relationship between neural wiring, regional heterogeneity and spatial embedding using spatial autocorrelation-preserving null models. We show that mixing between micro-architecturally diverse neuronal populations is supported by long-distance connections. Using meta-analytic decoding, we find that the arrangement of connectivity patterns with respect to biological annotations shape patterns of regional functional specialization. Specifically, regions that connect to biologically similar regions are associated with executive function; conversely, regions that connect with biologically dissimilar regions are associated with memory function. By bridging scales of cortical organization, from microscale attributes to macroscale connectivity, this work lays the foundation for next-generation annotated connectomics.

13 p.-6 fig., The yeast Ty1 retrotransposon integrates upstream of genes transcribed by RNA polymerase III (Pol III). Specificity of integration is mediated by an interaction between the Ty1 integrase (IN1) and Pol III, currently uncharacterized at the atomic level. We report cryo-EM structures of Pol III in complex with IN1, revealing a 16-residue segment at the IN1 C-terminus that contacts Pol III subunits AC40 and AC19, an interaction that we validate by in vivo mutational analysis. Binding to IN1 associates with allosteric changes in Pol III that may affect its transcriptional activity. The C-terminal domain of subunit C11, involved in RNA cleavage, inserts into the Pol III funnel pore, providing evidence for a two-metal mechanism during RNA cleavage. Additionally, ordering next to C11 of an N-terminal portion from subunit C53 may explain the connection between these subunits during termination and reinitiation. Deletion of the C53 N-terminal region leads to reduced chromatin association of Pol III and IN1, and a major fall in Ty1 integration events. Our data support a model in which IN1 binding induces a Pol III configuration that may favor its retention on chromatin, thereby improving the likelihood of Ty1 integration., This work was supported by the Agence Nationale de la Recherche (ANR-17-CE11-0025 to P.L., J.A., J.R. and C.F.-T.), the Spanish Ministry of Science/Agencia Estatal de Investigación (BFU2017-87397-P, RED2018-102467-T and PID2020-116722GB-I00 to C.F.-T.; PRE2018-087012 to A.P.-P.), intramural funding from CSIC (2020AEP152 and PIE-202120E047-Conexiones-Life to C. F.-T.), Fondation pour la Recherche Médicale (FRM-EQU202203014635 to P.L.; FRM-SPF20170938755 to A.A.-L.; FRM-ECO202206015504 to B.C.), and intramural funding from CNRS, Université Paris Cité and INSERM (to P.L.).

Lassa fever hits West African countries annually in the absence of licensed vaccine to limit the burden of this viral hemorrhagic fever. We previously developed MeV-NP, a single-shot vaccine protecting cynomolgus monkeys against divergent strains one month or more than a year before Lassa virus infection. Given the limited dissemination area during outbreaks and the risk of nosocomial transmission, a vaccine inducing rapid protection could be useful to protect exposed people during outbreaks in the absence of preventive vaccination. Here, we test whether the time to protection can be reduced after immunization by challenging measles virus pre-immune male cynomolgus monkeys sixteen or eight days after a single shot of MeV-NP. None of the immunized monkeys develop disease and they rapidly control viral replication. Animals immunized eight days before the challenge are the best controllers, producing a strong CD8 T-cell response against the viral glycoprotein. A group of animals was also vaccinated one hour after the challenge, but was not protected and succumbed to the disease as the control animals. This study demonstrates that MeV-NP can induce a rapid protective immune response against Lassa fever in the presence of MeV pre-existing immunity but can likely not be used as therapeutic vaccine.

Giant viruses (GVs) are a hotspot of unresolved controversies since their discovery, including the definition of “Virus” and their origin. While increasing knowledge of genome diversity has accumulated, GV functional genomics was largely neglected. Here, we describe an experimental framework to genetically modify nuclear GVs and their host Acanthamoeba castellanii using CRISPR/Cas9, shedding light on the evolution from small icosahedral viruses to amphora-shaped GVs. Ablation of the icosahedral major capsid protein in the phylogenetically-related mollivirus highlights a transition in virion shape and size. We additionally demonstrate the existence of a reduced core essential genome in pandoravirus, reminiscent of their proposed smaller ancestors. This proposed genetic expansion led to increased genome robustness, indicating selective pressures for adaptation to uncertain environments. Overall, we introduce new tools for manipulation of the unexplored genome of nuclear GVs and provide experimental evidence suggesting that viral gigantism has aroused as an emerging trait.

The cell nucleus is a primary target for intracellular bacterial pathogens to counteract immune responses and hijack host signalling pathways to cause disease. Here we identify two Brucella abortus effectors, NyxA and NyxB, that interfere with host protease SENP3, and this facilitates intracellular replication of the pathogen. The translocated Nyx effectors directly interact with SENP3 via a defined acidic patch (identified from the crystal structure of NyxB), preventing nucleolar localisation of SENP3 at late stages of infection. By sequestering SENP3, the effectors promote cytoplasmic accumulation of nucleolar AAA-ATPase NVL and ribosomal protein L5 (RPL5) in effector-enriched structures in the vicinity of replicating bacteria. The shuttling of ribosomal biogenesis-associated nucleolar proteins is inhibited by SENP3 and requires the autophagy-initiation protein Beclin1 and the SUMO-E3 ligase PIAS3. Our results highlight a nucleomodulatory function of two Brucella effectors and reveal that SENP3 is a crucial regulator of the subcellular localisation of nucleolar proteins during Brucella infection, promoting intracellular replication of the pathogen.

Funding Information: This study was partly supported by the Centre National d’Études Spatiale (CNES) through the project “Hydrodynamics of wet foams". A.S. acknowledges Véronique Trappe and Eric Dufresne for interesting discussions. Publisher Copyright: © 2023, The Author(s). Foams are unstable jammed materials. They evolve over timescales comparable to their “time of use", which makes the study of their destabilisation mechanisms crucial for applications. In practice, many foams are made from viscoelastic fluids, which are observed to prolong their lifetimes. Despite their importance, we lack understanding of the coarsening mechanism in such systems. We probe the effect of continuous phase viscoelasticity on foam coarsening with foamed emulsions. We show that bubble size evolution is strongly slowed down and foam structure hugely impacted. The main mechanisms responsible are the absence of continuous phase redistribution and a non-trivial link between foam structure and mechanical properties. These combine to give spatially heterogeneous coarsening. Beyond their importance in the design of foamy materials, the results give a macroscopic vision of phase separation in a viscoelastic medium.

Antigen binding by B cell receptors (BCR) on cognate B cells elicits a response that eventually leads to production of antibodies. However, it is unclear what the distribution of BCRs is on the naïve B cell and how antigen binding triggers the first step in BCR signaling. Using DNA-PAINT super-resolution microscopy, we find that most BCRs are present as monomers, dimers, or loosely associated clusters on resting B cells, with a nearest-neighbor inter-Fab distance of 20–30 nm. We leverage a Holliday junction nanoscaffold to engineer monodisperse model antigens with precision-controlled affinity and valency, and find that the antigen exerts agonistic effects on the BCR as a function of increasing affinity and avidity. Monovalent macromolecular antigens can activate the BCR at high concentrations, whereas micromolecular antigens cannot, demonstrating that antigen binding does not directly drive activation. Based on this, we propose a BCR activation model determined by the antigen footprint.

New satellite remote sensing and machine learning techniques offer untapped possibilities to monitor global biodiversity with unprecedented speed and precision. These efficiencies promise to reveal novel ecological insights at spatial scales which are germane to the management of populations and entire ecosystems. Here, we present a robust transferable deep learning pipeline to automatically locate and count large herds of migratory ungulates (wildebeest and zebra) in the Serengeti-Mara ecosystem using fine-resolution (38-50 cm) satellite imagery. The results achieve accurate detection of nearly 500,000 individuals across thousands of square kilometers and multiple habitat types, with an overall F1-score of 84.75% (Precision: 87.85%, Recall: 81.86%). This research demonstrates the capability of satellite remote sensing and machine learning techniques to automatically and accurately count very large populations of terrestrial mammals across a highly heterogeneous landscape. We also discuss the potential for satellite-derived species detections to advance basic understanding of animal behavior and ecology.

Mutations in glucocerebrosidase cause the lysosomal storage disorder Gaucher’s disease and are the most common risk factor for Parkinson’s disease. Therapies to restore the enzyme’s function in the brain hold great promise for treating the neurological implications. Thus, we developed blood-brain barrier penetrant therapeutic molecules by fusing transferrin receptor-binding moieties to β-glucocerebrosidase (referred to as GCase-BS). We demonstrate that these fusion proteins show significantly increased uptake and lysosomal efficiency compared to the enzyme alone. In a cellular disease model, GCase-BS rapidly rescues the lysosomal proteome and lipid accumulations beyond known substrates. In a mouse disease model, intravenous injection of GCase-BS leads to a sustained reduction of glucosylsphingosine and can lower neurofilament-light chain plasma levels. Collectively, these findings demonstrate the potential of GCase-BS for treating GBA1-associated lysosomal dysfunction, provide insight into candidate biomarkers, and may ultimately open a promising treatment paradigm for lysosomal storage diseases extending beyond the central nervous system.

The recent discovery of superconductivity in paramagnetic UTe2 turns spotlight on a serious candidate for spin-triplet state. To draw a complete picture of the superconducting state in UTe2 precise knowledge of the electronic properties of the 5 f states of Uranium is missing. We report on x-ray absorption and magnetic circular dichroism experiments performed at the U M4,5 edges at 2.7 K. At ambient pressure the 5 f electron count is found to be in-between 2.6 and 2.8. Partial delocalization of the 5 f electrons is further confirmed by the reduced value of the U orbital to spin magnetic moment ratio. The 5 f count is reduced by as large as 7 percent at the transition to a magnetically ordered state at Pc ≈ 1.5 GPa. At pressures above 4 GPa, the 5 f count increases back towards U3+ in the tetragonal phase. The observed “valence instabilities” and their interplay with magnetism seem to be important ingredients to understand the electronic structure in UTe2 in different phases.

Women of reproductive age are a group of particular concern with regards to vaccine uptake, related to their unique considerations of menstruation, fertility, and pregnancy. To obtain vaccine uptake data specific to this group, we obtained vaccine surveillance data from the Office for National Statistics, linked with COVID-19 vaccination status from the National Immunisation Management Service, England, from 8 Dec 2020 to 15 Feb 2021; data from 13,128,525 such women at population-level, were clustered by age (18–29, 30–39, and 40–49 years), self-defined ethnicity (19 UK government categories), and index of multiple deprivation (IMD, geographically-defined IMD quintiles). Here we show that among women of reproductive age, older age, White ethnicity and being in the least-deprived index of multiple deprivation are each independently associated with higher vaccine uptake, for first and second doses; however, ethnicity exerts the strongest influence (and IMD the weakest). These findings should inform future vaccination public messaging and policy.

Photosynthetic algae have evolved mechanisms to cope with suboptimal light and CO2 conditions. When light energy exceeds CO2 fixation capacity, Chlamydomonas reinhardtii activates photoprotection, mediated by LHCSR1/3 and PSBS, and the CO2 Concentrating Mechanism (CCM). How light and CO2 signals converge to regulate these processes remains unclear. Here, we show that excess light activates photoprotection- and CCM-related genes by altering intracellular CO2 concentrations and that depletion of CO2 drives these responses, even in total darkness. High CO2 levels, derived from respiration or impaired photosynthetic fixation, repress LHCSR3/CCM genes while stabilizing the LHCSR1 protein. Finally, we show that the CCM regulator CIA5 also regulates photoprotection, controlling LHCSR3 and PSBS transcript accumulation while inhibiting LHCSR1 protein accumulation. This work has allowed us to dissect the effect of CO2 and light on CCM and photoprotection, demonstrating that light often indirectly affects these processes by impacting intracellular CO2 levels.

Resumen (Objetivo) Se estudió la variación de las concentraciones del sulfuro de hidrógeno (H2S) y del amoniaco (NH3) en aire, en un sistema de tratamiento de aguas residuales en Costa Rica, para conocer el posible alcance de los olores producidos, con mediciones en el lugar y un modelo de dispersión de sustancias en el aire. (Metodología) Fueron realizados 13 muestreos en periodos de 12 horas y 24 horas, entre octubre del 2016 y febrero del 2017; con las mediciones de campo, se alimentó un modelo de dispersión. Se midieron los parámetros meteorológicos: dirección y velocidad de viento, radiación global, temperatura, porcentaje de humedad relativa, precipitación y presión atmosférica. Mediante el uso de los programas Aermed View y AERMOD, se demostró la dispersión de los gases alrededor de los puntos de emisión seleccionados en la planta de tratamiento. Al Aermet View se le incorporaron los parámetros de rugosidad superficial, la proporción de Bowen y el albedo para una zona rural. Los datos recolectados se incluyeron en AERMOD. (Resultados) La concentración de los gases emitidos por la planta se encuentra por debajo de los valores de percepción de estas sustancias, 0,70 µg/m3 (< 0,50 ppb) para el H2S y 26,6 µg/m3 (< 35,5 ppb) para el NH3. Se determinó que el canal de vertido es la fuente principal de emisión. Los gases generados se dispersaron hacia las comunidades vecinas de La Carpio, María Auxiliadora y Rincón Grande, en dirección noroeste; Carvajal Castro, Rossiter Carballo, Residencial Real Santamaría y Lagunilla, en dirección noreste, y la Comisión Nacional de Emergencia, en dirección sur. Los valores de error se encontraron en un ámbito entre el 5 % y el 48 % para el H2S y entre el 8 % y el 75 % para el NH3. El índice de concordancia (IC) mostró una similitud entre los valores predichos y los valores observados, tanto para el H2S como para el NH3. (Conclusiones) Las emisiones gaseosas de H2S y NH3 provenientes del sistema de tratamiento de aguas residuales no representan un riesgo para la salud ni el medio ambiente, en las poblaciones cercanas. Abstract (Objective) The variation of hydrogen sulfide (H2S) and ammonia (NH3) concentrations in air was studied in a wastewater treatment system in Costa Rica to obtain information about the dispersion of odors produced using on-site measurements and an air dispersion model. (Methodology) Thirteen samples were taken in periods of 12 hours and 24 hours between October 2016 and February 2017, and the measurements taken in the field were entered into a dispersion model. Meteorological parameters including direction and wind speed, global radiation, temperature, percentage of relative humidity, precipitation, and atmospheric pressure were recorded. Dispersion of gases around the selected emission points in the treatment plant was determined using the Aermed View and AERMOD programs. Data on roughness parameters, Bowen ratio and albedo for a rural area were incorporated into the Aermet View and the data collected was incorporated into the AERMOD model. (Results) The concentrations of gases emitted by the plant were below the perception values of these substances, 0.70 µg/m3 (< 0.50 ppb) for H2S and 26.6 µg/m3 (< 35.5 ppb) for NH3. The discharge channel is the main source of emissions; the gases emitted were dispersed to the neighboring communities of La Carpio, María Auxiliadora and Rincón Grande to the Northwest; Carvajal Castro, Rossiter Carballo, Residencial Real Santamaría and Lagunilla to the Northeast, and the National Emergency Commission to the South. Error values ranged between 5% and 48% for H2S and between 8% and 75% for NH3. The concordance index (CI) showed agreement between the predicted and observed values for both H2S and NH3. (Conclusions) H2S and NH3 emissions from the wastewater treatment system do not represent a risk to health or the environment for nearby populations. Resumo (Objetivo) A variação nas concentrações de sulfeto de hidrogênio (H2S) e amoníaco (NH3) no ar, em um sistema de tratamento de águas residuais na Costa Rica, para conhecer a possível extensão dos odores produzidos, com medições no local e um modelo de dispersão de substâncias no ar. (Metodologia). Foram realizadas treze amostragens em períodos de 12 horas e 24 horas, entre outubro de 2016 e fevereiro de 2017; com as medidas de campo, um modelo de dispersão foi alimentado. Os parâmetros meteorológicos foram medidos: direção e velocidade do vento, radiação global, temperatura, porcentagem de umidade relativa, precipitação e pressão atmosférica. Usando o Aermed View e o software AERMOD, foi demonstrada a dispersão de gases em torno dos pontos de emissão selecionados na estação de tratamento. Os parâmetros de rugosidade superficial, razão de Bowen e albedo para uma área rural foram incorporados na Aermet View. Os dados coletados foram incluídos no AERMOD. (Resultados) A concentração dos gases emitidos pela planta está abaixo dos valores de percepção para estas substâncias, 0,70 µg/m3 (< 0,50 ppb) para H2S e 26,6 µg/m3 (< 35,5 ppb) para NH3. O canal de deposição de descarte foi identificado como a principal fonte de emissões. Os gases gerados foram dispersos para as comunidades vizinhas de La Carpio, María Auxiliadora e Rincón Grande, na direção noroeste; Carvajal Castro, Rossiter Carballo, Residencial Real Santamaría e Lagunilla, na direção nordeste, e a Comissão Nacional de Emergência, na direção sul. Foram encontrados valores de erro entre 5% e 48% para o H2S e entre 8% e 75% para o NH3. O índice de concordância (CI) mostrou uma semelhança entre os valores previstos e observados tanto para o H2S quanto para o NH3. (Conclusões) As emissões gasosas de H2S y NH3 do sistema de tratamento de águas residuais não representam um risco sanitário e ambiental para as populações próximas.

Background: Pain is a very important factor in patient recovery and satisfaction. Following incision and drainage of perianal abscess, wound packing has been found to be very painful. The aim of this study is to compare packing the wound and not packing the wound after incision and drainage (I&D) of perianal abscess, taking into account recurrence rate, rate of occurrence of perianal fistula as well as post-operative pain. Materials and Method: Standard medical electronic databases were searched with the help of a local librarian and relevant published randomised controlled trials (RCT) were shortlisted according to the inclusion criteria. The summated outcome of post-operative pain score, recurrence rate, and rate of occurrence of perianal fistula was evaluated using the principles of meta-analysis on RevMan 5 statistical software. Result: Three RCTs on 490 patients undergoing I&D of perianal abscess were found suitable for this meta-analysis. In the random effects model analysis, the post operative pain score was statistically lower in NPG [risk ratio 0.66, 95%, CI (0.36, 0.97), Z=4.25, P=0.0001]. There was no heterogeneity [Tau2=0.15; chi2=9.32; df=6; I2=36 %; p=0.16] between the studies, however, statistically it was not significant. In addition, there was no statistical difference between the 2 groups in terms of recurrence of perianal abscess or the occurrence of perianal fistula [risk ratio 0.64, 95%, CI (0.31, 1.31), Z=1.23, P=0.22], [risk ratio 1.41, 95%, CI (0.89, 2.23), Z=1.47, P=0.14] respectively. Conclusion: Not packing the wound post I&D of perianal abscess is associated with significantly reduced VAS pain scores, which may result in improved recovery and patient satisfaction and has no effect on recurrence rate or the occurrence of perianal fistula. However, more RCTs recruiting a greater number of patients are required to endorse these findings.