Showing papers by "Aix-Marseille University published in 2021"

The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.

Abstract: The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood.

Abstract: In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy - Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.

JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles.

Abstract: JASPAR (http://jaspar.genereg.net/) is an open-access database containing manually curated, non-redundant transcription factor (TF) binding profiles for TFs across six taxonomic groups. In this 9th release, we expanded the CORE collection with 341 new profiles (148 for plants, 101 for vertebrates, 85 for urochordates, and 7 for insects), which corresponds to a 19% expansion over the previous release. We added 298 new profiles to the Unvalidated collection when no orthogonal evidence was found in the literature. All the profiles were clustered to provide familial binding profiles for each taxonomic group. Moreover, we revised the structural classification of DNA binding domains to consider plant-specific TFs. This release introduces word clouds to represent the scientific knowledge associated with each TF. We updated the genome tracks of TFBSs predicted with JASPAR profiles in eight organisms; the human and mouse TFBS predictions can be visualized as native tracks in the UCSC Genome Browser. Finally, we provide a new tool to perform JASPAR TFBS enrichment analysis in user-provided genomic regions. All the data is accessible through the JASPAR website, its associated RESTful API, the R/Bioconductor data package, and a new Python package, pyJASPAR, that facilitates serverless access to the data.

The carbohydrate-active enzyme database: functions and literature.

Abstract: Thirty years have elapsed since the emergence of the classification of carbohydrate-active enzymes in sequence-based families that became the CAZy database over 20 years ago, freely available for browsing and download at www.cazy.org. In the era of large scale sequencing and high-throughput Biology, it is important to examine the position of this specialist database that is deeply rooted in human curation. The three primary tasks of the CAZy curators are (i) to maintain and update the family classification of this class of enzymes, (ii) to classify sequences newly released by GenBank and the Protein Data Bank and (iii) to capture and present functional information for each family. The CAZy website is updated once a month. Here we briefly summarize the increase in novel families and the annotations conducted during the last 8 years. We present several important changes that facilitate taxonomic navigation, and allow to download the entirety of the annotations. Most importantly we highlight the considerable amount of work that accompanies the analysis and report of biochemical data from the literature.

Planck 2018 results - VI. Cosmological parameters (Corrigendum)

Abstract: Author(s): Aghanim, N; Akrami, Y; Ashdown, M; Aumont, J; Baccigalupi, C; Ballardini, M; Banday, AJ; Barreiro, RB; Bartolo, N; Basak, S; Battye, R; Benabed, K; Bernard, JP; Bersanelli, M; Bielewicz, P; Bock, JJ; Bond, JR; Borrill, J; Bouchet, FR; Boulanger, F; Bucher, M; Burigana, C; Butler, RC; Calabrese, E; Cardoso, JF; Carron, J; Challinor, A; Chiang, HC; Chluba, J; Colombo, LPL; Combet, C; Contreras, D; Crill, BP; Cuttaia, F; De Bernardis, P; De Zotti, G; Delabrouille, J; Delouis, JM; DI Valentino, E; DIego, JM; Dore, O; Douspis, M; Ducout, A; Dupac, X; Dusini, S; Efstathiou, G; Elsner, F; Enslin, TA; Eriksen, HK; Fantaye, Y; Farhang, M; Fergusson, J; Fernandez-Cobos, R; Finelli, F; Forastieri, F; Frailis, M; Fraisse, AA; Franceschi, E; Frolov, A; Galeotta, S; Galli, S; Ganga, K; Genova-Santos, RT; Gerbino, M; Ghosh, T; Gonzalez-Nuevo, J; Gorski, KM; Gratton, S; Gruppuso, A; Gudmundsson, JE; Hamann, J; Handley, W; Hansen, FK; Herranz, D; Hildebrandt, SR; Hivon, E; Huang, Z; Jaffe, AH; Jones, WC; Karakci, A; Keihanen, E; Keskitalo, R; Kiiveri, K; Kim, J; Kisner, TS | Abstract: In the original version, the bounds given in Eqs. (87a) and (87b) on the contribution to the early-time optical depth, (15,30), contained a numerical error in deriving the 95th percentile from the Monte Carlo samples. The corrected 95% upper bounds are: τ(15,30) l 0:018 (lowE, flat τ(15, 30), FlexKnot), (1) τ(15, 30) l 0:023 (lowE, flat knot, FlexKnot): (2) These bounds are a factor of 3 larger than the originally reported results. Consequently, the new bounds do not significantly improve upon previous results from Planck data presented in Millea a Bouchet (2018) as was stated, but are instead comparable. Equations (1) and (2) give results that are now similar to those of Heinrich a Hu (2021), who used the same Planck 2018 data to derive a 95% upper bound of 0.020 using the principal component analysis (PCA) model and uniform priors on the PCA mode amplitudes.

Autoantibodies neutralizing type I IFNs are present in ~ 4% of uninfected individuals over 70 years old and account for ~ 20% of COVID-19 deaths.

Abstract: Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.

Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer.

Abstract: PURPOSEImmunotherapy has revolutionized the treatment of advanced non–small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in o...

Integrating the evidence for a terrestrial carbon sink caused by increasing atmospheric CO2

Abstract: Atmospheric carbon dioxide concentration ([CO2 ]) is increasing, which increases leaf-scale photosynthesis and intrinsic water-use efficiency. These direct responses have the potential to increase plant growth, vegetation biomass, and soil organic matter; transferring carbon from the atmosphere into terrestrial ecosystems (a carbon sink). A substantial global terrestrial carbon sink would slow the rate of [CO2 ] increase and thus climate change. However, ecosystem CO2 responses are complex or confounded by concurrent changes in multiple agents of global change and evidence for a [CO2 ]-driven terrestrial carbon sink can appear contradictory. Here we synthesize theory and broad, multidisciplinary evidence for the effects of increasing [CO2 ] (iCO2 ) on the global terrestrial carbon sink. Evidence suggests a substantial increase in global photosynthesis since pre-industrial times. Established theory, supported by experiments, indicates that iCO2 is likely responsible for about half of the increase. Global carbon budgeting, atmospheric data, and forest inventories indicate a historical carbon sink, and these apparent iCO2 responses are high in comparison to experiments and predictions from theory. Plant mortality and soil carbon iCO2 responses are highly uncertain. In conclusion, a range of evidence supports a positive terrestrial carbon sink in response to iCO2 , albeit with uncertain magnitude and strong suggestion of a role for additional agents of global change.

Trained immunity, tolerance, priming and differentiation: distinct immunological processes.

Abstract: The similarities and differences between trained immunity and other immune processes are the subject of intense interrogation. Therefore, a consensus on the definition of trained immunity in both in vitro and in vivo settings, as well as in experimental models and human subjects, is necessary for advancing this field of research. Here we aim to establish a common framework that describes the experimental standards for defining trained immunity.

Democratising deep learning for microscopy with ZeroCostDL4Mic.

Abstract: Deep Learning (DL) methods are powerful analytical tools for microscopy and can outperform conventional image processing pipelines. Despite the enthusiasm and innovations fuelled by DL technology, the need to access powerful and compatible resources to train DL networks leads to an accessibility barrier that novice users often find difficult to overcome. Here, we present ZeroCostDL4Mic, an entry-level platform simplifying DL access by leveraging the free, cloud-based computational resources of Google Colab. ZeroCostDL4Mic allows researchers with no coding expertise to train and apply key DL networks to perform tasks including segmentation (using U-Net and StarDist), object detection (using YOLOv2), denoising (using CARE and Noise2Void), super-resolution microscopy (using Deep-STORM), and image-to-image translation (using Label-free prediction - fnet, pix2pix and CycleGAN). Importantly, we provide suitable quantitative tools for each network to evaluate model performance, allowing model optimisation. We demonstrate the application of the platform to study multiple biological processes.

(18)F-FDG brain PET hypometabolism in patients with long COVID

Abstract: In the context of the worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), some patients report functional complaints after apparent recovery from COVID-19. This clinical presentation has been referred as “long COVID.” We here present a retrospective analysis of 18F-FDG brain PET of long COVID patients from the same center with a biologically confirmed diagnosis of SARS-CoV-2 infection and persistent functional complaints at least 3 weeks after the initial infection. PET scans of 35 patients with long COVID were compared using whole-brain voxel-based analysis to a local database of 44 healthy subjects controlled for age and sex to characterize cerebral hypometabolism. The individual relevance of this metabolic profile was evaluated to classify patients and healthy subjects. Finally, the PET abnormalities were exploratory compared with the patients’ characteristics and functional complaints. In comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected). These metabolic clusters were highly discriminant to distinguish patients and healthy subjects (100% correct classification). These clusters of hypometabolism were significantly associated with more numerous functional complaints (brainstem and cerebellar clusters), and all associated with the occurrence of certain symptoms (hyposmia/anosmia, memory/cognitive impairment, pain and insomnia) (p < 0.05). In a more preliminary analysis, the metabolism of the frontal cluster which included the olfactory gyrus was worse in the 7 patients treated by ACE drugs for high blood pressure (p = 0.032), and better in the 3 patients that had used nasal decongestant spray at the infectious stage (p < 0.001). This study demonstrates a profile of brain PET hypometabolism in long COVID patients with biologically confirmed SARS-CoV-2 and persistent functional complaints more than 3 weeks after the initial infection symptoms, involving the olfactory gyrus and connected limbic/paralimbic regions, extended to the brainstem and the cerebellum. These hypometabolisms are associated with patients’ symptoms, with a biomarker value to identify and potentially follow these patients. The hypometabolism of the frontal cluster, which included the olfactory gyrus, seems to be linked to ACE drugs in patients with high blood pressure, with also a better metabolism of this olfactory region in patients using nasal decongestant spray, suggesting a possible role of ACE receptors as an olfactory gateway for this neurotropism.

Averages of b-hadron, c-hadron, and $$\tau $$-lepton properties as of 2018: Heavy Flavor Averaging Group (HFLAV)

Abstract: This paper reports world averages of measurements of b -hadron, c -hadron, and -lepton properties obtained by the Heavy Flavour Averaging Group using results available through September 2018. In rare cases, significant results obtained several months later are also used. For the averaging, common input parameters used in the various analyses are adjusted (rescaled) to common values, and known correlations are taken into account. The averages include branching fractions, lifetimes, neutral meson mixing parameters, violation parameters, parameters of semileptonic decays, and Cabibbo–Kobayashi–Maskawa matrix elements.

Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis.

Abstract: FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1-5. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2-CD44-SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.

COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study.

Abstract: Summary Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19 The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group) Severe disease was defined as that requiring admission to an intensive care unit or leading to death Secondary objectives were to analyse deaths and duration of hospital stay The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]) Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD This study is registered with ClinicalTrialsgov, NCT04353609 Findings Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66–6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46–0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55–3·19, p=0·53) Interpretation Rituximab therapy is associated with more severe COVID-19 Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases Funding None

An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 2: impacts on organisms and ecosystems.

Abstract: New information on the lethal and sublethal effects of neonicotinoids and fipronil on organisms is presented in this review, complementing the previous Worldwide Integrated Assessment (WIA) in 2015. The high toxicity of these systemic insecticides to invertebrates has been confirmed and expanded to include more species and compounds. Most of the recent research has focused on bees and the sublethal and ecological impacts these insecticides have on pollinators. Toxic effects on other invertebrate taxa also covered predatory and parasitoid natural enemies and aquatic arthropods. Little new information has been gathered on soil organisms. The impact on marine and coastal ecosystems is still largely uncharted. The chronic lethality of neonicotinoids to insects and crustaceans, and the strengthened evidence that these chemicals also impair the immune system and reproduction, highlights the dangers of this particular insecticidal class (neonicotinoids and fipronil), with the potential to greatly decrease populations of arthropods in both terrestrial and aquatic environments. Sublethal effects on fish, reptiles, frogs, birds, and mammals are also reported, showing a better understanding of the mechanisms of toxicity of these insecticides in vertebrates and their deleterious impacts on growth, reproduction, and neurobehaviour of most of the species tested. This review concludes with a summary of impacts on the ecosystem services and functioning, particularly on pollination, soil biota, and aquatic invertebrate communities, thus reinforcing the previous WIA conclusions (van der Sluijs et al. 2015).

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial

Abstract: Summary Background The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43–0·74], p Methods This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov , NCT02362594 , and EudraCT, 2014-004944-37. Findings Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9–69·5] in the pembrolizumab group vs 49·4% [44·8–53·8] in the placebo group; HR 0·60 [95% CI 0·49–0·73]; p Interpretation Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma. Funding Merck Sharp & Dohme.

Human impacts on global freshwater fish biodiversity.

Abstract: Freshwater fish represent one-fourth of the world’s vertebrates and provide irreplaceable goods and services but are increasingly affected by human activities. A new index, Cumulative Change in Biodiversity Facets, revealed marked changes in biodiversity in >50% of the world’s rivers covering >40% of the world’s continental surface and >37% of the world’s river length, whereas

Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma

Abstract: PURPOSEIn the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year effi...

Structural Biology in the Clouds: The WeNMR-EOSC Ecosystem

Abstract: Structural biology aims at characterizing the structural and dynamic properties of biological macromolecules with atomic details. Gaining insight into three dimensional structures of biomolecules and their interactions is critical for understanding the vast majority of cellular processes, with direct applications in health and food sciences. Since 2010, the WeNMR project (www.wenmr.eu) has implemented numerous web-based services to facilitate the use of advanced computational tools by researchers in the field, using the high throughput computing infrastructure provided by EGI. These services have been further developed in subsequent initiatives under H2020 projects and are now operating as Thematic Services in the European Open Science Cloud (EOSC) portal (www.eosc-portal.eu), sending >12 millions of jobs and using around 4000 CPU-years per year. Here we review 10 years of successful e-infrastructure solutions serving a large worldwide community of over 23,000 users to date, providing them with user-friendly, web-based solutions that run complex workflows in structural biology. The current set of active WeNMR portals are described, together with the complex backend machinery that allows distributed computing resources to be harvested efficiently.

Leading hadronic contribution to the muon magnetic moment from lattice QCD

Abstract: The standard model of particle physics describes the vast majority of experiments and observations involving elementary particles. Any deviation from its predictions would be a sign of new, fundamental physics. One long-standing discrepancy concerns the anomalous magnetic moment of the muon, a measure of the magnetic field surrounding that particle. Standard-model predictions1 exhibit disagreement with measurements2 that is tightly scattered around 3.7 standard deviations. Today, theoretical and measurement errors are comparable; however, ongoing and planned experiments aim to reduce the measurement error by a factor of four. Theoretically, the dominant source of error is the leading-order hadronic vacuum polarization (LO-HVP) contribution. For the upcoming measurements, it is essential to evaluate the prediction for this contribution with independent methods and to reduce its uncertainties. The most precise, model-independent determinations so far rely on dispersive techniques, combined with measurements of the cross-section of electron–positron annihilation into hadrons3–6. To eliminate our reliance on these experiments, here we use ab initio quantum chromodynamics (QCD) and quantum electrodynamics simulations to compute the LO-HVP contribution. We reach sufficient precision to discriminate between the measurement of the anomalous magnetic moment of the muon and the predictions of dispersive methods. Our result favours the experimentally measured value over those obtained using the dispersion relation. Moreover, the methods used and developed in this work will enable further increased precision as more powerful computers become available. A precise theoretical computation of the anomalous magnetic moment of the muon based on ab initio quantum chromodynamics and quantum electrodynamics calculations is presented, which favours the existing experimental values.

Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade.

Abstract: Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

Tumor-Infiltrating Natural Killer Cells

Abstract: Because of their potent antitumor activity and their proinflammatory role, natural killer (NK) cells are at the forefront of efforts to develop immuno-oncologic treatments. NK cells participate in immune responses to tumors by killing target cells and producing cytokines. However, in the immunosuppressive tumor microenvironment, NK cells become dysfunctional through exposure to inhibitory molecules produced by cancer cells, leading to tumor escape. We provide an overview of what is known about NK tumor infiltration and surveillance and about the mechanisms by which NK cells become dysfunctional. SIGNIFICANCE: The functions of tumor-infiltrating NK cells may be impaired. This review aims to describe the various mechanisms by which tumors alter NK-cell functions.

Economic, Mental Health, HIV Prevention and HIV Treatment Impacts of COVID-19 and the COVID-19 Response on a Global Sample of Cisgender Gay Men and Other Men Who Have Sex with Men.

Abstract: There is an urgent need to measure the impacts of COVID-19 among gay men and other men who have sex with men (MSM). We conducted a cross-sectional survey with a global sample of gay men and other MSM (n = 2732) from April 16, 2020 to May 4, 2020, through a social networking app. We characterized the economic, mental health, HIV prevention and HIV treatment impacts of COVID-19 and the COVID-19 response, and examined whether sub-groups of our study population are disproportionately impacted by COVID-19. Many gay men and other MSM not only reported economic and mental health consequences, but also interruptions to HIV prevention and testing, and HIV care and treatment services. These consequences were significantly greater among people living with HIV, racial/ethnic minorities, immigrants, sex workers, and socio-economically disadvantaged groups. These findings highlight the urgent need to mitigate the negative impacts of COVID-19 among gay men and other MSM.