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Contains fulltext : 290938.pdf (Publisher’s version ) (Open Access) The tricarboxylic acid cycle is the central pathway of energy production in eukaryotic cells and plays a key part in aerobic respiration throughout all kingdoms of life. One of the pivotal enzymes in this cycle is 2-oxoglutarate dehydrogenase complex (OGDHC), which generates NADH by oxidative decarboxylation of 2-oxoglutarate to succinyl-CoA. OGDHC is a megadalton protein complex originally thought to be assembled from three catalytically active subunits (E1o, E2o, E3). In fungi and animals, however, the protein MRPS36 has more recently been proposed as a putative additional component. Based on extensive cross-linking mass spectrometry data supported by phylogenetic analyses, we provide evidence that MRPS36 is an important member of the eukaryotic OGDHC, with no prokaryotic orthologues. Comparative sequence analysis and computational structure predictions reveal that, in contrast with bacteria and archaea, eukaryotic E2o does not contain the peripheral subunit-binding domain (PSBD), for which we propose that MRPS36 evolved as an E3 adaptor protein, functionally replacing the PSBD. We further provide a refined structural model of the complete eukaryotic OGDHC of approximately 3.45 MDa with novel mechanistic insights.

Closing the emissions gap between Nationally Determined Contributions (NDCs) and the global emissions levels needed to achieve the Paris Agreement’s climate goals will require a comprehensive package of policy measures. National and sectoral policies can help fill the gap, but success stories in one country cannot be automatically replicated in other countries. They need to be adapted to the local context. Here, we develop a new Bridge scenario based on nationally relevant, short-term measures informed by interactions with country experts. These good practice policies are rolled out globally between now and 2030 and combined with carbon pricing thereafter. We implement this scenario with an ensemble of global integrated assessment models. We show that the Bridge scenario closes two-thirds of the emissions gap between NDC and 2 °C scenarios by 2030 and enables a pathway in line with the 2 °C goal when combined with the necessary long-term changes, i.e. more comprehensive pricing measures after 2030. The Bridge scenario leads to a scale-up of renewable energy (reaching 52%–88% of global electricity supply by 2050), electrification of end-uses, efficiency improvements in energy demand sectors, and enhanced afforestation and reforestation. Our analysis suggests that early action via good-practice policies is less costly than a delay in global climate cooperation., Comprehensive policy measures are needed to close the emissions gap between Nationally Determined Contributions and emissions goals of the Paris Agreement. Here the authors present a Bridge scenario that may aid in closing the emissions gap by 2030.

Numerosity, the set size of a group of items, helps guide behaviour and decisions. Non-symbolic numerosities are represented by the approximate number system. However, distinct behavioural performance suggests that small numerosities, i.e. subitizing range, are implemented differently in the brain than larger numerosities. Prior work has shown that neural populations selectively responding (i.e. hemodynamic responses) to small numerosities are organized into a network of topographical maps. Here, we investigate how neural populations respond to large numerosities, well into the ANS. Using 7 T fMRI and biologically-inspired analyses, we found a network of neural populations tuned to both small and large numerosities organized within the same topographic maps. These results demonstrate a continuum of numerosity preferences that progressively cover both the subitizing range and beyond within the same numerosity map, suggesting a single neural mechanism. We hypothesize that differences in map properties, such as cortical magnification and tuning width, underlie known differences in behaviour., Here, the authors show that the brain represents small and large numerosity ranges in a continuous topographic map, in line with the idea that differences in map properties underlie differences in perception.

Micropipette aspiration (MPA) is an essential tool in mechanobiology; however, its potential is far from fully exploited. The traditional MPA technique has limited temporal and spatial resolution and requires extensive post processing to obtain the mechanical fingerprints of samples. Here, we develop a MPA system that measures pressure and displacement in real time with sub-nanometer resolution thanks to an interferometric readout. This highly sensitive MPA system enables studying the nanoscale behavior of soft biomaterials under tension and their frequency-dependent viscoelastic response., Beradi et al. establish a micropipette aspiration platform which enables sensitive real-time viscoelastic measurements of soft biomaterials. They use it to characterize the rheological behavior of cells and soft materials at very small deformations, yielding consistent and reproducible values.

The Nationally Determined Contributions (NDCs) represent the world's first effort toward the Paris Agreement goal of keeping global temperature increase well below 2 °C and pursuing 1.5 °C. Little is known about how much the proposed mitigation efforts can reduce the risks and economic damages from unabated climate change and about the consequences if key emitters drop the Paris Agreement. Here, we use CLIMRISK, an integrated assessment model designed to support climate policy at the global, national, and subnational scales where mitigation and adaptation policy decisions are made. We characterize the consequences of unabated climate change and the benefits of current climate policy proposals by means of probabilistic estimates of the economic damages of climate change and uni- and multivariate dynamic climate risk indices at a detailed spatial resolution. The results presented reveal that the economic costs and risks are highly unequally distributed between and within countries and larger than previously estimated when warming in urban areas and temporal persistence of impacts are accounted for. Costs and risks can be significantly limited by strict implementation of NDCs, but increase noticeably under noncompliance by large emitters, like the United States.

Scientific data analyses often combine several computational tools in automated pipelines, or workflows. Thousands of such workflows have been used in the life sciences, though their composition has remained a cumbersome manual process due to a lack of standards for annotation, assembly, and implementation. Recent technological advances have returned the long-standing vision of automated workflow composition into focus. This article summarizes a recent Lorentz Center workshop dedicated to automated composition of workflows in the life sciences. We survey previous initiatives to automate the composition process, and discuss the current state of the art and future perspectives. We start by drawing the “big picture” of the scientific workflow development life cycle, before surveying and discussing current methods, technologies and practices for semantic domain modelling, automation in workflow development, and workflow assessment. Finally, we derive a roadmap of individual and community-based actions to work toward the vision of automated workflow development in the forthcoming years. A central outcome of the workshop is a general description of the workflow life cycle in six stages: 1) scientific question or hypothesis, 2) conceptual workflow, 3) abstract workflow, 4) concrete workflow, 5) production workflow, and 6) scientific results. The transitions between stages are facilitated by diverse tools and methods, usually incorporating domain knowledge in some form. Formal semantic domain modelling is hard and often a bottleneck for the application of semantic technologies. However, life science communities have made considerable progress here in recent years and are continuously improving, renewing interest in the application of semantic technologies for workflow exploration, composition and instantiation. Combined with systematic benchmarking with reference data and large-scale deployment of production-stage workflows, such technologies enable a more systematic process of workflow development than we know today. We believe that this can lead to more robust, reusable, and sustainable workflows in the future.

Background: Afucosylated IgG1 responses have only been found against membrane-embedded epitopes, including anti-S in SARS-CoV-2 infections. These responses, intrinsically protective through enhanced Fc gamma RIIIa binding, can also trigger exacerbated pro-inflammatory responses in severe COVID-19. We investigated if the BNT162b2 SARS-CoV-2 mRNA also induced afucosylated IgG responses. Methods: Blood from vaccinees during the first vaccination wave was collected. Liquid chromatography-Mass spectrometry (LC-MS) was used to study anti-S IgG1 Fc glycoprofiles. Responsiveness of alveolar-like macrophages to produce proinflammatory cytokines in presence of sera and antigen was tested. Antigen-specific B cells were characterized and glycosyltransferase levels were investigated by Fluorescence-Activated Cell Sorting (FACS). Findings: Initial transient afucosylated anti-S IgG1 responses were found in naive vaccinees, but not in antigen -experienced ones. All vaccinees had increased galactosylated and sialylated anti-S IgG1. Both naive and antigen -experienced vaccinees showed relatively low macrophage activation potential, as expected, due to the low antibody levels for naive individuals with afucosylated IgG1, and low afucosylation levels for antigen-experienced individuals with high levels of anti-S. Afucosylation levels correlated with FUT8 expression in antigen-specific plasma cells in naive individuals. Interestingly, low fucosylation of anti-S IgG1 upon seroconversion correlated with high anti-S IgG levels after the second dose. Interpretation: Here, we show that BNT162b2 mRNA vaccination induces transient afucosylated anti-S IgG1 responses in naive individuals. This observation warrants further studies to elucidate the clinical context in which potent afucosylated responses would be preferred. Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The amnion is an extraembryonic tissue that evolutionarily allowed embryos of all amniotes to develop in a transient and local aquatic environment. Despite the importance of this tissue, very little is known about its formation and its molecular characteristics. In this review, we have compared the basic organization of the extraembryonic membranes in amniotes and describe the two types of amniogenesis, folding and cavitation. We then zoom in on the atypical development of the amnion in mice that occurs via the formation of a single posterior amniochorionic fold. Moreover, we consolidate lineage tracing data to better understand the spatial and temporal origin of the progenitors of amniotic ectoderm, and visualize the behaviour of their descendants in the extraembryonic–embryonic junctional region. This analysis provides new insight on amnion development and expansion. Finally, using an online-available dataset of single-cell transcriptomics during the gastrulation period in mice, we provide bioinformatic analysis of the molecular signature of amniotic ectoderm and amniotic mesoderm. The amnion is a tissue with unique biomechanical properties that deserves to be better understood. This article is part of the theme issue ‘Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom’.

Alternatively-activated, M2-like tumor-associated macrophages (TAM) strongly contribute to tumor growth, invasiveness and metastasis. Technologies to disable the pro-tumorigenic function of these TAMs are of high interest to immunotherapy research. Here we show that by designing engineered nanoliposomes bio-mimicking peroxidated phospholipids that are recognised and internalised by scavenger receptors, TAMs can be targeted. Incorporation of phospholipids possessing a terminal carboxylate group at the sn-2 position into nanoliposome bilayers drives their uptake by M2 macrophages with high specificity. Molecular dynamics simulation of the lipid bilayer predicts flipping of the sn-2 tail towards the aqueous phase, while molecular docking data indicates interaction of the tail with Scavenger Receptor Class B type 1 (SR-B1). In vivo, the engineered nanoliposomes are distributed specifically to M2-like macrophages and, upon delivery of the STAT6 inhibitor (AS1517499), zoledronic acid or muramyl tripeptide, these cells promote reduction of the premetastatic niche and/or tumor growth. Altogether, we demonstrate the efficiency and versatility of our engineered “tail-flipping” nanoliposomes in a pre-clinical model, which paves the way to their development as cancer immunotherapeutics in humans.

The original version of this Article contained an incorrect reference to the database used in the study (reference no. 73). This has been corrected in both the PDF and HTML versions of the Article.

Liquid crystal (LC) phases are in between solids and liquids with properties of both. Nematic LCs composed of rod-like molecules or particles exhibit long-range orientational order, yielding characteristic birefringence, but they lack positional order, allowing them to flow like a liquid. This combination of properties as well as their sensitivity to external fields make nematic LCs fundamental for optical applications e.g. liquid crystal displays (LCDs). When rod-like particles become bent, spontaneous bend deformations arise in the LC, leading to geometric frustration which can be resolved by complementary twist or splay deformations forming intriguing twist-bend (NTB) and splay-bend (NSB) nematic phases. Here, we show experimentally that the elusive NSB phases can be stabilized in systems of polydisperse micron-sized bent silica rods. Our results open avenues for the realization of NTB and NSB phases of colloidal and molecular LCs.

Cryo-electron microscopy has become an essential tool to understand structure and function of biological samples. Especially for pathogens, such as disease-causing bacteria and viruses, insights gained by cryo-EM can aid in developing cures. However, due to the biosafety restrictions of pathogens, samples are often treated by chemical fixation to render the pathogen inert, affecting the ultrastructure of the sample. Alternatively, researchers use in vitro or ex vivo models, which are non-pathogenic but lack the complexity of the pathogen of interest. Here we show that ultraviolet-C (UVC) radiation applied at cryogenic temperatures can be used to eliminate or dramatically reduce the infectivity of Vibrio cholerae and the bacterial virus, the ICP1 bacteriophage. We show no discernable structural impact of this treatment of either sample using two cryo-EM methods: cryo-electron tomography followed by sub-tomogram averaging, and single particle analysis (SPA). Additionally, we applied the UVC irradiation to the protein apoferritin (ApoF), which is a widely used test sample for high-resolution SPA studies. The UVC-treated ApoF sample resulted in a 2.1 Å structure indistinguishable from an untreated published map. This research demonstrates that UVC treatment is an effective and inexpensive addition to the cryo-EM sample preparation toolbox., Depelteau et al. present a new method to inactivate cryo-EM samples from pathogenic organisms before imaging using ultraviolet-C radiation in cryogenic conditions. This method allows for the inexpensive preparation of cryo-EM samples with no discernable structural impact of the treatment.

Microtubules are cytoskeletal polymers that separate chromosomes during mitosis and serve as rails for intracellular transport and organelle positioning. Manipulation of microtubules is widely used in cell and developmental biology, but tools for precise subcellular spatiotemporal control of microtubules are currently lacking. Here, we describe a light-activated system for localized recruitment of the microtubule-severing enzyme katanin. This system, named opto-katanin, uses targeted illumination with blue light to induce rapid, localized, and reversible microtubule depolymerization. This tool allows precise clearing of a subcellular region of microtubules while preserving the rest of the microtubule network, demonstrating that regulation of katanin recruitment to microtubules is sufficient to control its severing activity. The tool is not toxic in the absence of blue light and can be used to disassemble both dynamic and stable microtubules in primary neurons as well as in dividing cells. We show that opto-katanin can be used to locally block vesicle transport and to clarify the dependence of organelle morphology and dynamics on microtubules. Specifically, our data indicate that microtubules are not required for the maintenance of the Golgi stacks or the tubules of the endoplasmic reticulum but are needed for the formation of new membrane tubules. Finally, we demonstrate that this tool can be applied to study the contribution of microtubules to cell mechanics by showing that microtubule bundles can exert forces constricting the nucleus.

eLife is changing its editorial process to emphasize public reviews and assessments of preprints by eliminating accept/reject decisions after peer review.

Binding to the neonatal Fc receptor (FcRn) extends serum half-life of IgG, and antagonizing this interaction is a promising therapeutic approach in IgG-mediated autoimmune diseases. Fc-MST-HN, designed for enhanced FcRn binding capacity, has not been evaluated in the context of a full-length antibody, and the structural properties of the attached Fab regions might affect the FcRn-mediated intracellular trafficking pathway. Here we present a comprehensive comparative analysis of the IgG salvage pathway between two full-size IgG1 variants, containing wild type and MST-HN Fc fragments, and their Fc-only counterparts. We find no evidence of Fab-regions affecting FcRn binding in cell-free assays, however, cellular assays show impaired binding of full-size IgG to FcRn, which translates into improved intracellular FcRn occupancy and intracellular accumulation of Fc-MST-HN compared to full size IgG1-MST-HN. The crystal structure of Fc-MST-HN in complex with FcRn provides a plausible explanation why the Fab disrupts the interaction only in the context of membrane-associated FcRn. Importantly, we find that Fc-MST-HN outperforms full-size IgG1-MST-HN in reducing IgG levels in cynomolgus monkeys. Collectively, our findings identify the cellular membrane context as a critical factor in FcRn biology and therapeutic targeting.

Extracellular vesicles can modulate diverse processes ranging from proliferation and tissue repair, to chemo-resistance and cellular differentiation. With the advent of tissue and immunological targeting, extracellular vesicles are also increasingly viewed as promising vectors to deliver peptide-based cancer antigens to the human immune system. Despite the clinical relevance and therapeutic potential of such ‘cell-free’ approaches, the natural antigen presentation landscape exported in extracellular vesicles is still largely uncharted, due to the challenging nature of such preparations and analyses. In the context of therapeutic vesicle production, a critical evaluation of the similarity in vesicular antigen presentation is also urgently needed. In this work, we compared the HLA-I peptide ligandomes of extracellular vesicles against that of whole-cells of the same cell line. We found that extracellular vesicles not only over-represent HLA-B complexes and peptide ligands, but also cysteinylated peptides that may modulate immune responses. Collectively, these findings describe the pre-existing provision of vesicular HLA complexes that may be utilized to carry peptide vaccines, as well as the propensity for different peptide and post-translationally modified ligands to be presented, and will outline critical considerations in devising novel EV vaccination strategies., Bauzá-Martinez et al. analyzed the HLA-I peptide ligandome in extracellular vesicles (EVs) from an EBV-immortalized B cell line, JY, and compare HLA-I-binding peptides recovered from EVs to those recovered from whole-cells. The authors report an enrichment for HLA-B-binding peptides and for post-translationally modified cysteinylated peptides in EVs as compared to whole-cells.

The charging and dissolution of mineral surfaces in contact with flowing liquids are ubiquitous in nature, as most minerals in water spontaneously acquire charge and dissolve. Mineral dissolution has been studied extensively under equilibrium conditions, even though non-equilibrium phenomena are pervasive and substantially affect the mineral-water interface. Here we demonstrate using interface-specific spectroscopy that liquid flow along a calcium fluoride surface creates a reversible, spatial charge gradient, with decreasing surface charge downstream of the flow. The surface charge gradient can be quantitatively accounted for by a reaction-diffusion-advection model, which reveals that the charge gradient results from a delicate interplay between diffusion, advection, dissolution, and desorption/adsorption. The underlying mechanism is expected to be valid for a wide variety of systems, including groundwater flows in nature and microfluidic systems., Comment: 25 pages, 8 figures, Supplementary Information: 21 pages, 7 figures

With the addition of the compstatin-based complement C3 inhibitor pegcetacoplan, another class of complement targeted therapeutics have recently been approved. Moreover, compstatin derivatives with enhanced pharmacodynamic and pharmacokinetic profiles are in clinical development (e.g., Cp40/AMY-101). Despite this progress, the target binding and inhibitory modes of the compstatin family remain incompletely described. Here, we present the crystal structure of Cp40 complexed with its target C3b at 2.0-Å resolution. Structure-activity-relationship studies rationalize the picomolar affinity and long target residence achieved by lead optimization, and reveal a role for structural water in inhibitor binding. We provide explanations for the narrow species specificity of this drug class and demonstrate distinct target selection modes between clinical compstatin derivatives. Functional studies provide further insight into physiological complement activation and corroborate the mechanism of its compstatin-mediated inhibition. Our study may thereby guide the application of existing and development of next-generation compstatin analogs.

Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1β, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis.

The development of T lymphocytes in the thymus and their stem cell precursors in the bone marrow is controlled by Wnt signaling in strictly regulated, cell-type specific dosages. In this study, we investigated levels of canonical Wnt signaling during hematopoiesis and T cell development within the Axin2-mTurquoise2 reporter. We demonstrate active Wnt signaling in hematopoietic stem cells (HSCs) and early thymocytes, but also in more mature thymic subsets and peripheral T lymphocytes. Thymic epithelial cells displayed particularly high Wnt signaling, suggesting an interesting crosstalk between thymocytes and thymic epithelial cells (TECs). Additionally, reporter mice allowed us to investigate the loss of Axin2 function, demonstrating decreased HSC repopulation upon transplantation and the partial arrest of early thymocyte development in Axin2Tg/Tg full mutant mice. Mechanistically, loss of Axin2 leads to supraphysiological Wnt levels that disrupt HSC differentiation and thymocyte development.

Polyolefin catalysts are characterized by their hierarchically complex nature, which complicates studies on the interplay between the catalyst and formed polymer phases. Here, the missing link in the morphology gap between planar model systems and industrially relevant spherical catalyst particles is introduced through the use of a spherical cap Ziegler-type catalyst model system for the polymerization of ethylene. More specifically, a moisture-stable LaOCl framework with enhanced imaging contrast has been designed to support the TiCl4 pre-active site, which could mimic the behaviour of the highly hygroscopic and industrially used MgCl2 framework. As a function of polymerization time, the fragmentation behaviour of the LaOCl framework changed from a mixture of the shrinking core (i.e., peeling off small polyethylene fragments at the surface) and continuous bisection (i.e., internal cleavage of the framework) into dominantly a continuous bisection model, which is linked to the evolution of the estimated polyethylene volume and the fraction of crystalline polyethylene formed. The combination of the spherical cap model system and the used advanced micro-spectroscopy toolbox, opens the route for high-throughput screening of catalyst functions with industrially relevant morphologies on the nano-scale.

The Membrane Attack Complex (MAC or C5b-9) is an important effector of the immune system to kill invading microbes. MAC is formed when complement enzymes on the bacterial surface convert complement component C5 into C5b. Although the MAC is a membrane-inserted complex, soluble forms of MAC (sMAC, or terminal complement complex (TCC)) are often detected in sera of patients suffering from infections. Consequently, sMAC has been proposed as a biomarker, but it remains unclear when and how it is formed during infections. Here, we studied mechanisms of MAC formation on bacteria and found that sMAC is primarily formed in human serum by bacteria resistant to MAC-dependent killing. Surprisingly, C5 was converted into C5b more potently by MAC-resistant compared to MAC-sensitiveEscherichia colistrains. Both the increase in C5 conversion and sMAC generation were linked to the expression of lipopolysaccharide (LPS) O-Antigen in the bacterial outer membrane. In addition, we found that MAC precursors are released from the surface of MAC-resistant bacteria during MAC assembly. Release of MAC precursors from bacteria induced lysis of bystander human erythrocytes in the absence of other serum components. However, serum regulators vitronectin (Vn) and clusterin (Clu) can prevent this bystander lysis. Combining size exclusion chromatography with mass spectrometry profiling, we show that sMAC released from bacteria in serum is a heterogeneous mixture of complexes composed of C5b-8, up to 3 copies of C9 and multiple copies of Vn and Clu. Altogether, our data provide molecular insight into how sMAC is generated during bacterial infections. This fundamental knowledge could form the basis for exploring the use of sMAC as biomarker.

Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, including epithelial ovarian cancer. Patients often experience several response-relapse events, until tumors become resistant and life expectancy drops to 12-15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, leaving patients with limited options. Serine biosynthesis has been linked to cancer growth and poor prognosis in various cancer types, however its role in platinum-resistant ovarian cancer is not known. Here, we show that a subgroup of resistant tumors decreases phosphoglycerate dehydrogenase (PHGDH) expression at relapse after platinum-based chemotherapy. Mechanistically, we observe that this phenomenon is accompanied by a specific oxidized nicotinamide adenine dinucleotide (NAD+) regenerating phenotype, which helps tumor cells in sustaining Poly (ADP-ribose) polymerase (PARP) activity under platinum treatment. Our findings reveal metabolic vulnerabilities with clinical implications for a subset of platinum resistant ovarian cancers. ispartof: NATURE COMMUNICATIONS vol:13 issue:1 ispartof: location:England status: published

The envelope glycoprotein GP of the ebolaviruses is essential for host cell attachment and entry. It is also the primary target of the protective and neutralizing antibody response in both natural infection and vaccination. GP is heavily glycosylated with up to 17 predicted N-linked sites, numerous O-linked glycans in its disordered mucin-like domain (MLD), and three predicted C-linked mannosylation sites. Glycosylation of GP is important for host cell attachment to cell-surface lectins, as well as GP stability and fusion activity. Moreover, it has been shown to shield GP from neutralizing activity of serum antibodies. Here, we use mass spectrometry-based glycoproteomics to profile the site-specific glycosylation patterns of ebolavirus GP. We detect up to 16 unique O-linked glycosylation sites in the mucin-like domain, as well as two O-linked sites in the head and glycan cap domains of the receptor-binding GP1 subunit. Multiple O-linked glycans are observed at the S/T residues of N-linked glycosylation sequons, suggesting possible crosstalk between the two types of modifications. We also confirmed the presence of C-mannosylation at W288 in the context of trimeric GP. We find heterogenous, complex N-linked glycosylation at the majority of predicted sites as expected. By contrast, the two conserved sites N257 and N563 are enriched in unprocessed high-mannose and hybrid glycans, suggesting a role in host-cell attachment via DC-SIGN/L-SIGN. We discuss our findings in the context of antibody recognition to show how glycans contribute to and restrict neutralization epitopes. This information on how N-, O-, and C-linked glycans together build the heterogeneous glycan shield of GP can guide future immunological studies and functional interpretation of ebolavirus GP-antibody interactions.

The major microtubule-organizing center (MTOC) in animal cells, the centrosome, comprises a pair of centrioles surrounded by pericentriolar material (PCM), which nucleates and anchors microtubules. Centrosome assembly depends on PCM binding to centrioles, PCM self-association and dynein­mediated PCM transport, but the self-assembly properties of PCM in interphase cells are poorly understood. Here, we used experiments and modeling to study centriole-independent features of interphase PCM assembly. We showed that when centrioles are lost due to PLK4 depletion or inhibition, dynein-based PCM transport and PCM self-clustering are sufficient to form a single compact MTOC, which generates a dense radial microtubule array. Interphase PCM self-assembly depends on γ-tubulin, pericentrin, CDK5RAP2 and ninein, but not NEDD1, CEP152 or CEP192. Formation of a compact acentriolar MTOC is inhibited by AKAP450-dependent PCM recruitment to the Golgi or by randomly organized CAMSAP2-stabilized microtubules, which keep PCM mobile and prevent its coalescence. Linking of CAMSAP2 to a minus-end-directed motor leads to the formation of an MTOC, but MTOC compaction requires cooperation with pericentrin-containing self-clustering PCM. Our data reveal that interphase PCM contains a set of components that can self-assemble into a compact structure and organize microtubules, but PCM self-organization is sensitive to motor-and microtubule-based rearrangement.

To optimize costs and reproductive success, rhesus macaques in biomedical primate research facilities are often peer-reared. Older, dependent infants are typically removed from their natal group to enhance female reproduction. The minimal husbandry age-norm of infant removal is ten months. These practices deviate from species-specific behavior and may reduce welfare, suggesting a trade-off between female reproduction and welfare. However, the effect of breeding group type and rearing history on female reproductive success (i.e., birth rate; inter-birth interval (IBI); offspring survival) is unclear. This retrospective study investigated whether group type (i.e., peer groups versus multigenerational groups) and rearing history (i.e., peer- or hand-reared; group-reared with peer- or hand-reared mother; group-reared) affected female reproductive success in captive rhesus macaques. Data on female reproduction between 1996 and 2019 were collected at the Biomedical Primate Research Centre, Rijswijk. Birth rates were higher in multigenerational breeding groups than in peer groups. Moreover, group-reared females had higher offspring survival than peer- or hand-reared females. IBI was not affected by breeding group type or female rearing history. However, females in both peer and multigenerational breeding groups typically conceived earlier after giving birth than the husbandry infant removal age-norm of ten months. Thus, infant removal at an age of ten months does not enhance a female’s reproduction. Altogether, female reproduction and non-human primate welfare can simultaneously be optimized through multigenerational breeding groups and group-rearing.

Biofuels are currently the only available bulk renewable fuel. They have, however, limited expansion potential due to high land requirements and associated risks for biodiversity, food security, and land conflicts. We therefore propose to increase output from ethanol refineries in a land-neutral methanol pathway: surplus CO2-streams from fermentation are combined with H2 from renewably powered electrolysis to synthesize methanol. We illustrate this pathway with the Brazilian sugarcane ethanol industry using a spatio-temporal model. The fuel output of existing ethanol generation facilities can be increased by 43%–49% or ~100 TWh without using additional land. This amount is sufficient to cover projected growth in Brazilian biofuel demand in 2030. We identify a trade-off between renewable energy generation technologies: wind power requires the least amount of land whereas a mix of wind and solar costs the least. In the cheapest scenario, green methanol is competitive to fossil methanol at an average carbon price of 95€ tCO2−1.

Carrier dynamics affects photocatalytic systems, but direct and real-time observations in an element-specific and energy-level-specific manner are challenging. In this study, we demonstrate that the dynamics of photo-generated holes in metal oxides can be directly probed by using femtosecond X-ray absorption spectroscopy at an X-ray free-electron laser. We identify the energy level and life time of holes with a long life time (230 pico-seconds) in nano-crystal materials. We also observe that trapped holes show an energy distribution in the bandgap region with a formation time of 0.3 pico-seconds and a decay time of 8.0 pico-seconds at room temperature. We corroborate the dynamics of the electrons by using X-ray absorption spectroscopy at the metal L-edges in a consistent explanation with that of the holes.

Reporting of outcome variables by caregivers in welfare studies is commonplace but is open to subjective bias and so requires validation. Biases can occur in either direction: familiarity with an animal allows a deeper insight into welfare problems, but also can lead to reticence in admitting that an animal in one's care is experiencing problems. Here, we aim to validate owner-reporting of plumage condition of pet parrots, including those with self-inflicted feather-damaging behaviour (FDB), by comparing owners’ scores of feather condition with those of two independent raters, blind to the owners’ and each other's assessments. We surveyed pet parrot owners to collect data on basic demographics and feather condition, and requested four standardised photographs of birds. We received 259 responses (17% of the 1,521 people contacted); 78 sets of images of appropriate quality for assessment by raters were provided. Mean percentage agreement between owners’ and raters’ scores was mostly fair to substantial using Cohen's kappa; however, raters scored a greater proportion of feather damage than did owners. Overall, our results indicate owner-reporting of feather condition, including FDB, to be generally reliable and consistent with independent assessment of photographs. As the use of photographs can be limited by image quality, a failure to represent the long-term state of a parrot, and the potential for incorrect recording if assessed without relevant information (eg on moulting), this evidence that owner-reports can be reliable opens the door for larger-scale surveys of the extent of welfare-relevant problems.

SUMMARYProtein import into the endoplasmic reticulum (ER) is essential for about 30% of the human proteome. It involves targeting of precursor proteins to the ER and insertion into or translocation across the ER membrane. Furthermore, it relies on signals in the precursor polypeptides and components, which read the signals and facilitate their targeting to a protein-conducting channel in the ER membrane, the Sec61 complex. Compared to the SRP- and TRC-dependent pathways, little is known about the SRP-independent/SND pathway. Our aim was to identify additional components and characterize the client spectrum of the human SND pathway. The established strategy of combining depletion of the central hSnd2-component from HeLa cells with proteomic- and differential protein abundance-analysis was used. The SRP and TRC targeting pathways were analyzed in comparison. TMEM109 was characterized as hSnd3. Unlike SRP but similar to TRC, the SND clients are predominantly membrane proteins with N-terminal, central, or C-terminal targeting signals.

Maximizing the catalytic activity of single-atom catalysts is vital for the application of single-atom catalysts in industrial water-alkali electrolyzers, yet the modulation of the catalytic properties of single-atom catalysts remains challenging. Here, we construct strain-tunable sulphur vacancies around single-atom Ru sites for accelerating the alkaline hydrogen evolution reaction of single-atom Ru sites based on a nanoporous MoS2-based Ru single-atom catalyst. By altering the strain of this system, the synergistic effect between sulphur vacancies and Ru sites is amplified, thus changing the catalytic behavior of active sites, namely, the increased reactant density in strained sulphur vacancies and the accelerated hydrogen evolution reaction process on Ru sites. The resulting catalyst delivers an overpotential of 30 mV at a current density of 10 mA cm−2, a Tafel slope of 31 mV dec−1, and a long catalytic lifetime. This work provides an effective strategy to improve the activities of single-atom modified transition metal dichalcogenides catalysts by precise strain engineering., The modulation of single-atom catalyst properties for industrial applications remains challenging. Here, authors use strain engineering to amplify the synergistic effect between MoS2’s sulphur vacancies and single-atom Ru sites and accelerate H2 evolution electrocatalysis.

For a long time, solid-state nuclear magnetic resonance (ssNMR) has been employed to study complex biomolecular systems at the detailed chemical, structural, or dynamic level. Recent progress in high-resolution and high-sensitivity ssNMR, in combination with innovative sample preparation and labeling schemes, offers novel opportunities to study proteins in their native setting irrespective of the molecular tumbling rate. This protocol describes biochemical preparation schemes to obtain cellular samples of both soluble as well as insoluble or membrane-associated proteins in bacteria. To this end, the protocol is suitable for studying a protein of interest in both whole cells and in cell envelope or isolated membrane preparations. In the first stage of the procedure, an appropriate strain of Escherichia coli (DE3) is transformed with a plasmid of interest harboring the protein of interest under the control of an inducible T7 promoter. Next, the cells are adapted to grow in minimal (M9) medium. Before the growth enters stationary phase, protein expression is induced, and shortly thereafter, the native E. coli RNA polymerase is inhibited using rifampicin for targeted labeling of the protein of interest. The cells are harvested after expression and prepared for ssNMR rotor filling. In addition to conventional 13C/15N-detected ssNMR, we also outline how these preparations can be readily subjected to multidimensional ssNMR experiments using dynamic nuclear polarization (DNP) or proton (1H) detection schemes. We estimate that the entire preparative procedure until NMR experiments can be started takes 3–5 days. A new protocol for solid-state NMR of soluble and membrane proteins in E. coli, in both whole cells and isolated membrane fractions. The procedure describes conventional 13C/15N ssNMR as well as sensitivity-enhanced DNP-ssNMR and 1H-detected ssNMR.

The axon initial segment (AIS) is a critical microdomain for action potential initiation and implicated in the regulation of neuronal excitability during activity-dependent plasticity. While structural AIS plasticity has been suggested to fine-tune neuronal activity when network states change, whether it acts in vivo as a homeostatic regulatory mechanism in behaviorally relevant contexts remains poorly understood. Using the mouse whisker-to-barrel pathway as a model system in combination with immunofluorescence, confocal analysis and electrophysiological recordings, we observed bidirectional AIS plasticity in cortical pyramidal neurons. Furthermore, we find that structural and functional AIS remodeling occurs in distinct temporal domains: Long-term sensory deprivation elicits an AIS length increase, accompanied with an increase in neuronal excitability, while sensory enrichment results in a rapid AIS shortening, accompanied by a decrease in action potential generation. Our findings highlight a central role of the AIS in the homeostatic regulation of neuronal input-output relations., The axon initial segment (AIS) is critical for action potential initiation and implicated in the regulation of neuronal excitability. The authors describe bidirectional AIS plasticity in a behaviourally relevant context, revealing that the AIS acts in vivo as a homeostatic regulatory domain.

Inland waters (rivers, lakes and ponds) are important conduits for the emission of terrestrial carbon in Arctic permafrost landscapes. These emissions are driven by turnover of contemporary terrestrial carbon and additional pre-aged (Holocene and late-Pleistocene) carbon released from thawing permafrost soils, but the magnitude of these source contributions to total inland water carbon fluxes remains unknown. Here we present unique simultaneous radiocarbon age measurements of inland water CO2, CH4 and dissolved and particulate organic carbon in northeast Siberia during summer. We show that >80% of total inland water carbon was contemporary in age, but pre-aged carbon contributed >50% at sites strongly affected by permafrost thaw. CO2 and CH4 were younger than dissolved and particulate organic carbon, suggesting emissions were primarily fuelled by contemporary carbon decomposition. Our findings reveal that inland water carbon emissions from permafrost landscapes may be more sensitive to changes in contemporary carbon turnover than the release of pre-aged carbon from thawing permafrost.

Tumor heterogeneity is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug-resistant cells, where tumor-specific human leukocyte antigen (HLA) peptide ligands are promising leads to invoke targeted anti-tumor responses. Here, we investigate the variability in HLA class I peptide presentation between different clonal cells of the same colorectal cancer patient, using an organoid system. While clone-specific differences in HLA peptide presentation were observed, broad inter-clone variability was even more prevalent (15–25%). By coupling organoid proteomics and HLA peptide ligandomics, we also found that tumor-specific ligands from DNA damage control and tumor suppressor source proteins were prominently presented by tumor cells, coinciding likely with the silencing of such cytoprotective functions. Collectively, these data illustrate the heterogeneous HLA peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden., Immunotherapy may exploit alternative vulnerabilities of drug resistant cells. Here, the authors show that the HLA peptide presentation landscape is heterogeneous even within one individual, hinting that a multi-peptide vaccination approach against highly conserved tumor suppressors may be needed.

KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (

In the open ocean, calcium carbonates are mainly found in two mineral forms. Calcite, the least soluble, is widespread at the seafloor, while aragonite, the more soluble, is rarely preserved in marine sediments. Despite its greater solubility, research has shown that aragonite, whose contribution to global pelagic calcification could be at par with that of calcite, is able to reach the deep-ocean. If large quantities of aragonite settle and dissolve at the seafloor, this represents a large source of alkalinity that buffers the deep ocean and favours the preservation of less soluble calcite, acting as a deep-sea, carbonate version of galvanization. Here, we investigate the role of aragonite dissolution on the early diagenesis of calcite-rich sediments using a novel 3D, micrometric-scale reactive-transport model combined with 3D, X-ray tomography structures of natural aragonite and calcite shells. Results highlight the important role of diffusive transport in benthic calcium carbonate dissolution, in agreement with recent work. We show that, locally, aragonite fluxes to the seafloor could be sufficient to suppress calcite dissolution in the top layer of the seabed, possibly causing calcite recrystallization. As aragonite producers are particularly vulnerable to ocean acidification, the proposed galvanizing effect of aragonite could be weakened in the future, and calcite dissolution at the sediment-water interface will have to cover a greater share of CO2 neutralization.

This study reports the discovery of dense sponge gardens across the peaks of permanently ice-covered, extinct volcanic seamounts of the Langseth Ridge and on the remnants of a now extinct seep ecosystem. Using approaches to sample and infer food and energy sources to this ice-covered community, the authors suggest that the sponges use refractory organic matter trapped in the extinct seep community on which they sit. The Central Arctic Ocean is one of the most oligotrophic oceans on Earth because of its sea-ice cover and short productive season. Nonetheless, across the peaks of extinct volcanic seamounts of the Langseth Ridge (87 degrees N, 61 degrees E), we observe a surprisingly dense benthic biomass. Bacteriosponges are the most abundant fauna within this community, with a mass of 460 g C m(-2) and an estimated carbon demand of around 110 g C m(-2) yr(-1), despite export fluxes from regional primary productivity only sufficient to provide

Rational catalyst design is crucial toward achieving more energy-efficient and sustainable catalytic processes. Here the authors report a data-driven approach for understanding catalytic reactions mechanisms in dilute bimetallic catalysts by combining X-ray absorption spectroscopy with activity studies and kinetic modeling.Rational catalyst design is crucial toward achieving more energy-efficient and sustainable catalytic processes. Understanding and modeling catalytic reaction pathways and kinetics require atomic level knowledge of the active sites. These structures often change dynamically during reactions and are difficult to decipher. A prototypical example is the hydrogen-deuterium exchange reaction catalyzed by dilute Pd-in-Au alloy nanoparticles. From a combination of catalytic activity measurements, machine learning-enabled spectroscopic analysis, and first-principles based kinetic modeling, we demonstrate that the active species are surface Pd ensembles containing only a few (from 1 to 3) Pd atoms. These species simultaneously explain the observed X-ray spectra and equate the experimental and theoretical values of the apparent activation energy. Remarkably, we find that the catalytic activity can be tuned on demand by controlling the size of the Pd ensembles through catalyst pretreatment. Our data-driven multimodal approach enables decoding of reactive structures in complex and dynamic alloy catalysts.

Previous studies reported contrasting conclusions concerning bonobo prosociality, which are likely due to differences in the experimental design, the social dynamics among subjects and characteristics of the subjects themselves. Two hypotheses have been proposed to explain the occurrence of prosociality in animals: the cooperative breeding hypothesis and the self-domestication hypothesis. While the former predicts low levels of prosociality in bonobos because they are non-cooperative breeders, the latter predicts high levels of prosociality because self-domestication has been proposed to select for high levels of tolerance in this species. Here, we presented a group of thirteen bonobos with two platform food-provisioning tasks: the prosocial choice task (PCT) and the group service paradigm (GSP). The latter has so far never been applied to bonobos. To allow for free choice of participation and partner, we implemented both tasks in a group setting. Like in previous PCT studies, bonobos did not choose the prosocial option more often when a group member could benefit vs not benefit. In the GSP, where food provisioning is costly, only subadult bonobos showed a limited amount of food provisioning, which was much lower than what was previously reported for chimpanzees. In both experiments, adult subjects were highly motivated to obtain rewards for themselves, suggesting that bonobos behaved indifferently to the gains of group members. We suggest that previous positive food-provisioning prosociality results in bonobos are mainly driven by the behaviour of subadult subjects. The lack of prosociality in this study corresponds to the hypothesis that proactive food provisioning co-occurs with cooperative breeding and suggests that proactive prosociality might not be part of the self-domestication syndrome in bonobos. ispartof: Peerj vol:10 pages:e12849-e12849 status: published

Auxin signaling and patterning is an inherently complex process, involving polarized auxin transport, metabolism, and signaling, its effect on developmental zones, as well as growth rates, and the feedback between all these different aspects. This complexity has led to an important role for computational modeling in unraveling the multifactorial roles of auxin in plant developmental and adaptive processes. Here we discuss the basic ingredients of auxin signaling and patterning models for root development as well as a series of key modeling studies in this area. These modeling studies have helped elucidate how plants use auxin signaling to compute the size of their root meristem, the direction in which to grow, and when and where to form lateral roots. Importantly, these models highlight how auxin, through patterning of and collaborating with other factors, can fulfill all these roles simultaneously.

Expansion microscopy (ExM) is a powerful technique to overcome the diffraction limit of light microscopy that can be applied in both tissues and cells. In ExM, samples are embedded in a swellable polymer gel to physically expand the sample and isotropically increase resolution in x, y and z. The maximum resolution increase is limited by the expansion factor of the gel, which is four-fold for the original ExM protocol. Variations on the original ExM method have been reported that allow for greater expansion factors but at the cost of ease of adoption or versatility. Here, we systematically explore the ExM recipe space and present a novel method termed Ten-fold Robust Expansion Microscopy (TREx) that, like the original ExM method, requires no specialized equipment or procedures. We demonstrate that TREx gels expand ten-fold, can be handled easily, and can be applied to both thick mouse brain tissue sections and cultured human cells enabling high-resolution subcellular imaging with a single expansion step. Furthermore, we show that TREx can provide ultrastructural context to subcellular protein localization by combining antibody-stained samples with off-the-shelf small molecule stains for both total protein and membranes.

Establishment of correct synaptic connections is a crucial step during neural circuitry formation. The Teneurin family of neuronal transmembrane proteins promotes cell–cell adhesion via homophilic and heterophilic interactions, and is required for synaptic partner matching in the visual and hippocampal systems in vertebrates. It remains unclear how individual Teneurins form macromolecular cis- and trans-synaptic protein complexes. Here, we present a 2.7 Å cryo-EM structure of the dimeric ectodomain of human Teneurin4. The structure reveals a compact conformation of the dimer, stabilized by interactions mediated by the C-rich, YD-shell, and ABD domains. A 1.5 Å crystal structure of the C-rich domain shows three conserved calcium binding sites, and thermal unfolding assays and SAXS-based rigid-body modeling demonstrate that the compactness and stability of Teneurin4 dimers are calcium-dependent. Teneurin4 dimers form a more extended conformation in conditions that lack calcium. Cellular assays reveal that the compact cis-dimer is compatible with homomeric trans-interactions. Together, these findings support a role for teneurins as a scaffold for macromolecular complex assembly and the establishment of cis- and trans-synaptic interactions to construct functional neuronal circuits.

Transforming carbon dioxide into valuable chemicals and fuels, is a promising tool for environmental and industrial purposes. Here, we present catalysts comprising of cobalt (oxide) nanoparticles stabilized on various support oxides for hydrocarbon production from carbon dioxide. We demonstrate that the activity and selectivity can be tuned by selection of the support oxide and cobalt oxidation state. Modulated excitation (ME) diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) reveals that cobalt oxide catalysts follows the hydrogen-assisted pathway, whereas metallic cobalt catalysts mainly follows the direct dissociation pathway. Contrary to the commonly considered metallic active phase of cobalt-based catalysts, cobalt oxide on titania support is the most active catalyst in this study and produces 11% C2+ hydrocarbons. The C2+ selectivity increases to 39% (yielding 104 mmol h−1 gcat−1 C2+ hydrocarbons) upon co-feeding CO and CO2 at a ratio of 1:2 at 250 °C and 20 bar, thus outperforming the majority of typical cobalt-based catalysts., Catalytic conversion of CO2 into valuable hydrocarbons is a promising way to mitigate climate change. This work uncovers that cobalt oxide nanoparticles on a titania carrier produce more C2+ hydrocarbons than their metallic cobalt counterpart by following a different reaction mechanism.

Dominance hierarchies typically emerge in systems where group members regularly encounter and compete for resources. In birds, the ‘open’ and dynamic structure of foraging groups may prevent the emergence of structured hierarchies, although this assumption have hardly been tested. We report on agonistic data for ravensCorvus corax, collected over two 18-month periods for 183 marked individuals of a wild (fluid) population and 51 birds from six captive (stable) groups. We show that the dominance structure (steep and transitive) in wild foraging groups is strikingly similar to that found in captivity. In the wild, we found that higher ranks are mainly occupied by males, older and more aggressive individuals that also tend to receive fewer aggressions. Exploring the mechanisms sustaining the wild dominance structure, we confirmed that males are more aggressive than females and, with age, tend to receive fewer aggressions than females. Males that are about to leave the foraging groups for some months are less aggressive than newcomers or locals, while newcomers are specifically targeted by aggressions in their first year (as juveniles). Taken together, our results indicate that the socially dynamic conditions ravens face during foraging do not hinder, but provide opportunities for, using (advanced) social cognition.This article is part of the theme issue ‘The centennial of the pecking order: current state and future prospects for the study of dominance hierarchies’.

Percolation is a process that impairs network connectedness by deactivating links or nodes. This process features a phase transition that resembles paradigmatic critical transitions in epidemic spreading, biological networks, traffic and transportation systems. Some biological systems, such as networks of neural cells, actively respond to percolation-like damage, which enables these structures to maintain their function after degradation and aging. Here we study percolation in networks that actively respond to link damage by adopting a mechanism resembling synaptic scaling in neurons. We explain critical transitions in such active networks and show that these structures are more resilient to damage as they are able to maintain a stronger connectedness and ability to spread information. Moreover, we uncover the role of local rescaling strategies in biological networks and indicate a possibility of designing smart infrastructures with improved robustness to perturbations., Link damages and failures can break the functionality of the whole complex network. Inspired by biological systems that respond to damages, the authors propose a mathematical model revealing the effect of homeostatic response to damage of links to keep the network’s global function.

Behavioral responses to novelty, including fear and subsequent avoidance of novel stimuli, i.e., neophobia, determine how animals interact with their environment. Neophobia aids in navigating risk and impacts on adaptability and survival. There is variation within and between individuals and species; however, lack of large-scale, comparative studies critically limits investigation of the socio-ecological drivers of neophobia. In this study, we tested responses to novel objects and food (alongside familiar food) versus a baseline (familiar food alone) in 10 corvid species (241 subjects) across 10 labs worldwide. There were species differences in the latency to touch familiar food in the novel object and novel food conditions relative to the baseline. Four of seven socio-ecological factors influenced object neophobia: (1) use of urban habitat (versus not), (2) territorial pair versus family group sociality, (3) large versus small maximum flock size, and (4) moderate versus specialized caching (whereas range, hunting live animals, and genus did not), while only maximum flock size influenced food neophobia. We found that, overall, individuals were temporally and contextually repeatable (i.e., consistent) in their novelty responses in all conditions, indicating neophobia is a stable behavioral trait. With this study, we have established a network of corvid researchers, demonstrating potential for further collaboration to explore the evolution of cognition in corvids and other bird species. These novel findings enable us, for the first time in corvids, to identify the socio-ecological correlates of neophobia and grant insight into specific elements that drive higher neophobic responses in this avian family group. Introduction Results - Species differences - Effect of socio-ecological factors - Individual temporal and contextual repeatability Discussion STAR★Methods

The importance of fatty acid (FA) metabolism in cancer is well-established, yet the mechanisms underlying metabolic reprogramming remain elusive. Here, we identify tetraspanin CD37, a prognostic marker for aggressive B-cell lymphoma, as essential membrane-localized inhibitor of FA metabolism. Deletion of CD37 on lymphoma cells results in increased FA oxidation shown by functional assays and metabolomics. Furthermore, CD37-negative lymphomas selectively deplete palmitate from serum in mouse studies. Mechanistically, CD37 inhibits the FA transporter FATP1 through molecular interaction. Consequently, deletion of CD37 induces uptake and processing of exogenous palmitate into energy and essential building blocks for proliferation, and inhibition of FATP1 reverses this phenotype. Large lipid deposits and intracellular lipid droplets are observed in CD37-negative lymphoma tissues of patients. Moreover, inhibition of carnitine palmitoyl transferase 1 A significantly compromises viability and proliferation of CD37-deficient lymphomas. Collectively, our results identify CD37 as a direct gatekeeper of the FA metabolic switch in aggressive B-cell lymphoma.Tetraspanin CD37 deficiency has been reported as a prognostic marker for aggressive B-cell lymphoma. Here, the authors show that CD37 interacts with the fatty acid transporter 1 to inhibit palmitate uptake and its deficiency leads to increased fatty acid metabolism which promotes tumorigenesis in B-cell lymphoma.

BackgroundImmunoglobulin G1 (IgG1) effector functions are impacted by the structure of fragment crystallizable (Fc) tail-linked N-glycans. Low fucosylation levels on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein specific (anti-S) IgG1 has been described as a hallmark of severe coronavirus disease 2019 (COVID-19) and may lead to activation of macrophages via immune complexes thereby promoting inflammatory responses, altogether suggesting involvement of IgG1 Fc glycosylation modulated immune mechanisms in COVID-19.MethodsIn this prospective, observational single center cohort study, IgG1 Fc glycosylation was analyzed by liquid chromatography – mass spectrometry following affinity capturing from serial plasma samples of 159 SARS-CoV-2 infected patients.FindingsAt baseline close to disease onset, anti-S IgG1 glycosylation was highly skewed when compared to total plasma IgG1. A rapid, general reduction in glycosylation skewing was observed during the disease course. Low anti-S IgG1 galactosylation and sialylation as well as high bisection were early hallmarks of disease severity, whilst high galactosylation and sialylation and low bisection were found in patients with low disease severity. In line with these observations, anti-S IgG1 glycosylation correlated with various inflammatory markers.InterpretationAssociation of low galactosylation, sialylation as well as high bisection with disease severity suggests that Fc-glycan modulated interactions contribute to disease mechanism. Further studies are needed to understand how anti-S IgG1 glycosylation may contributes to disease mechanism and to evaluate its biomarker potential.FundingThis project received funding from the European Commission’s Horizon2020 research and innovation program for H2020-MSCA-ITN IMforFUTURE, under grant agreement number 721815.Research in contextEvidence before this studyAntibody glycosylation against the spike (S) protein of patients infected with severe acute respiratory syndrome SARS-CoV-2 has been reported as a potentially important determinant of COVID-19 disease severity. Studies have hitherto focused on afucosylation, a modification on immunoglobulin G1 (IgG) Fc-tail-linked N-glycans that enhances effector functions. Most of these studies featured limited sample numbers or were imperfectly matched with respect to demographic and other important confounding factors. Our lab has contributed to some of these studies, and we additionally searched for research articles on PubMed and Google Scholar from January 2020 to October 2021. To date, only two groups studied anti-S IgG1 glycosylation, which resulted in overall three publications found. However, none of these groups found a severity marker between hospitalized non-ICU and ICU patients or studied dynamic changes. Instead, exclusively fucosylation at the first available timepoint has been associated with disease severity between severely ill inpatients and mild outpatients.Added value of this studyIn this prospective, observational single center cohort study, we investigated the severity marker potential of anti-S IgG1 glycosylation in severe and mild hospitalized COVID-19 cases, and correlated these findings with numerous inflammation and clinical markers. Our study reveals low galactosylation and sialylation as well as high bisection on anti-S IgG1 as early hallmarks of severe COVID-19, after correction for age and sex effects. In line with these observations, anti-S IgG1 glycosylation correlated with many inflammatory markers. As days since onset is one of the major confounders of anti-S IgG1 glycosylation due to its highly dynamic nature, we additionally confirmed our findings in time-matched patient subgroups. We believe anti-S IgG1 glycosylation may be applicable for patient stratification upon hospitalization.Implications of all the available evidenceDemographic factors as well as temporal differences should be taken into consideration when analyzing IgG1 glycosylation of COVID-19 patients. Anti-S IgG1 glycosylation is highly dynamic, but is a promising early severity marker in COVID-19.