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We present the rare case of a 51-year-old male diagnosed with a solitary fibrous tumor (SFT) of the prostate, along with a concurrent low-grade prostate adenocarcinoma (Gleason score 3 + 3, Grade Group 1). The diagnosis was confirmed by positive immunohistochemical markers, including CD34, BCL2, and STAT6, and molecular analysis showing a NAB2-STAT6 fusion. Following successful surgical management and the simultaneous diagnosis of a pulmonary relapse from a prior thyroid carcinoma, the patient remains under clinical surveillance. This is particularly significant given the patient's history of multiple tumors, including Hodgkin's lymphoma, papillary thyroid carcinoma, prostate cancer, and SFT.

Summary: Background: Insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease (MASLD) in people living with HIV (PLHIV) remain limited. Plasma proteomics holds promise for biomarker discovery and the elucidation of biological mechanisms. Methods: We performed cross-sectional analyses on data from 1036 virally suppressed PLHIV using antiretroviral treatment (ART) from the Dutch multi-centre 2000HIV cohort. Participants underwent transient elastography to assess liver steatosis (controlled attenuation parameter (CAP) ≥263 dB/m) and -fibrosis (liver stiffness measurement (LSM) ≥7.0 kPa). Plasma protein concentrations (n = 2367) (Olink® Explore Panel) were compared between PLHIV with vs. without liver steatosis and PLHIV with vs. without fibrosis. Enriched pathways (using GO, KEGG and Reactome libraries) and correlations with clinical characteristics were assessed, and analyses were stratified by BMI category. In addition, concentrations of 242 proteins were compared between individuals (“controls”) with and without liver steatosis (ratio of methylene:methylene and water >5.6% on magnetic resonance spectroscopy) from a separate cohort (300-OB), all having a BMI >26 kg/m2. Findings: Steatosis and fibrosis were associated with 67/2367 (2.2%) and 17/2367 (0.7%) differentially expressed proteins (DEP), respectively, enriched in mostly metabolic pathways. Immunoglobulin superfamily member 9 (IGSF9) was amongst the top DEP associated with both steatosis and fibrosis. Stratifying by BMI revealed 8/2367 DEP associated with steatosis in lean- and 12/2367 DEP in overweight/obese individuals, with two shared DEP (IGSF9 and GHR). Conversely, protein signatures of overweight/obese PLHIV (32/242 DEP) and overweight/obese HIV-uninfected individuals (32/242 DEP) exhibited substantial overlap with 16 shared DEP. Notably, DEP correlated with HIV characteristics in lean individuals but not in overweight/obese PLHIV. Interpretation: Lean and overweight/obese PLHIV exhibit distinct proteomic signatures associated with liver steatosis, with the former being more strongly correlated with HIV-specific factors and ART. In addition, we identified a protein, IGSF9, strongly related to liver fibrosis and steatosis across BMI categories. Funding: The 2000HIV study is funded by ViiV Healthcare.

Summary: Brief exposure of monocytes to atherogenic molecules, such as oxidized lipoproteins, triggers a persistent pro-inflammatory phenotype, named trained immunity. In mice, transient high-fat diet leads to trained immunity, which aggravates atherogenesis. We hypothesized that a single high-fat challenge in humans induces trained immunity. In a randomized controlled cross-over study, 14 healthy individuals received a high-fat or reference shake, and blood was drawn before and after 1, 2, 4, 6, 24, and 72 h. Incubation of donor monocytes with the post-high-fat-shake serum induced trained immunity, regulated via Toll-like receptor 4. This was not mediated via triglyceride-rich lipoproteins, C12, 14, and 16, or metabolic endotoxemia. In vivo, however, the high-fat challenge did not affect monocyte phenotype and function. We conclude that a high-fat challenge leads to alterations in the serum composition that have the potential to induce trained immunity in vitro. However, this does not translate into a (persistent) hyperinflammatory monocyte phenotype in vivo.

Summary: Trained immunity is characterized by histone modifications and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to heightened responsiveness to secondary stimuli. Although our understanding of the molecular regulation of trained immunity has increased, the role of adaptive immune cells herein remains largely unknown. Here, we show that T cells modulate trained immunity via cluster of differentiation 40-tissue necrosis factor receptor-associated factor 6 (CD40-TRAF6) signaling. CD40-TRAF6 inhibition modulates functional, transcriptomic, and metabolic reprogramming and modifies histone 3 lysine 4 trimethylation associated with trained immunity. Besides in vitro studies, we reveal that single-nucleotide polymorphisms in the proximity of CD40 are linked to trained immunity responses in vivo and that combining CD40-TRAF6 inhibition with cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)-mediated co-stimulatory blockade induces long-term graft acceptance in a murine heart transplantation model. Combined, our results reveal that trained immunity is modulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells and that this can be leveraged for therapeutic purposes.

Peatland degradation causes a number of environmental problems ranging from greenhouse gas (GHG) emissions to subsidence and ecosystem loss. Degraded peatlands, covering just 0.3 % of Earth’s land area (500,000 km2), disproportionately contribute 5 % of GHG emissions, exacerbating the climate crisis. Once degraded, restoring peatland ecosystem functions often presents a considerable challenge because degradation affects several interconnected components in peatlands: the peat body, hydrology, and vegetation. The planning and implementation of effective peatland restoration strategies requires the accurate mapping of degradation. This review examines how remote sensing has been used to examine the components of peatland degradation. A conceptual 3D space was created using the three components of peat, hydrology, and vegetation. Within this three-dimensional space, five groups of studies were identified, representing each one of the three dimensions individually, or addressing two or three of them simultaneously. Of 115 relevant articles, 54 % solely addressed vegetation degradation, 18 % evaluated two dimensions equally, while just 10 % of all studies examined all three dimensions. These results highlight a lack of remote sensing-based research that considers all aspects of peatland degradation and their interdependence simultaneously. By synthesizing our findings into three descriptive peatland degradation scenarios (a boreal landscape, a temperate large peatland complex and a temperate small raised bog), we present rapid and efficient methods and resources for a more holistic approach to degradation mapping and monitoring. Consequently, such comprehensive assessments integrating different historical and current remote sensing data should be carried out more frequently. They allow the visualization of ecological consequences of peatland degradation and promote peatland restoration in all parts of these tripartite ecosystems.

Summary: Intra-tumor heterogeneity, i.e., the presence of diverse cell types and subpopulations within tumors, presents a significant obstacle in cancer treatment due to its negative consequences for resistance to therapy and disease recurrence. However, the mechanisms that underlie intra-tumor heterogeneity and result in the plethora of different cancer cells within a single lesion remain poorly understood. Here, we leverage the SW480 cell line as a model system to investigate the molecular and functional diversity of colon cancer cells. Through a combination of fluorescence-activated cell sorting (FACS) analysis and transcriptomic profiling, we identified three distinct subpopulations, namely resident cancer stem cells (rCSCs), migratory CSCs (mCSCs), and high-relapse cells (HRCs). These subpopulations show varying Wnt signaling levels and gene expression profiles mirroring their stem-like and functional properties. Examination of publicly available spatial transcriptomic data confirms the presence of these subpopulations in patient-derived cancers and reveals their distinct spatial distribution relative to the tumor microenvironment.

Summary: The routine need for myonuclear turnover in skeletal muscle, together with more sporadic demands for hypertrophy and repair, are performed by resident muscle stem cells called satellite cells. Muscular dystrophies are characterized by muscle wasting, stimulating chronic repair/regeneration by satellite cells. Here, we derived and validated transcriptomic signatures for satellite cells, myoblasts/myocytes, and myonuclei using publicly available murine single cell RNA-Sequencing data. Our signatures distinguished disease from control in transcriptomic data from several muscular dystrophies including facioscapulohumeral muscular dystrophy (FSHD), Duchenne muscular dystrophy, and myotonic dystrophy type I. For FSHD, the expression of our gene signatures correlated with direct counts of satellite cells on muscle sections, as well as with increasing clinical and pathological severity. Thus, our gene signatures enable the investigation of myogenesis in bulk transcriptomic data from muscle biopsies. They also facilitate study of muscle regeneration in transcriptomic data from human muscle across health and disease.

In 2011, MoorFutures® were introduced as the first standard for generating credits from peatland rewetting. We developed methodologies to quantify ecosystem services before and after rewetting with a focus on greenhouse gas emissions, water quality, evaporative cooling and mire-typical biodiversity. Both standard and premium approaches to assess these services were developed, and tested in the rewetted polder Kieve (NE-Germany). The standard approaches are default tier 1 estimation procedures, which require little time and few, mainly vegetation data. Based on the Greenhouse gas Emission Site Type (GEST) approach, emissions decreased from 1,306 t CO2e in the baseline scenario to 532 t CO2e in the project scenario, whereas 5 years after rewetting they were assessed to be 543 t CO2e per year. Nitrate release assessed via Nitrogen Emission Site Types (NEST) was estimated to decrease from 1,088 kg N (baseline) to 359 kg N (project), and appeared to be 309 kg N per year 5 years after rewetting. The heat flux − determined with Evapotranspiration Energy Site Types (EEST) – decreased from 6,691 kW (baseline) to 1,926 kW (project), and was 2,250 kW per year 5 years after rewetting. Mire-specific biodiversity was estimated to increase from very low (baseline) to high (project), but was only low 5 years after rewetting. The premium approaches allow quantifying a particular ecosystem service with higher accuracy by measuring or modelling. The approaches presented here have been elaborated for North-Germany but can be adapted for other regions. We encourage scientists to use our research as a model for assessing peatland ecosystem services including biodiversity in other geographical regions. Using vegetation mapping and indicator values derived from meta-analyses is a cost-efficient and robust approach to inform payment for ecosystem services schemes and to support conservation planning at regional to global scales.

Summary: Background: Endogenous steroid hormones have significant effects on inflammatory and immune processes, but the immunological activities of steroidogenesis precursors remain largely unexplored. Methods: We conducted a systematic approach to examine the association between steroid hormones profile and immune traits in a cohort of 534 healthy volunteers. Serum concentrations of steroid hormones and their precursors (cortisol, progesterone, testosterone, androstenedione, 11-deoxycortisol and 17-OH progesterone) were determined by liquid chromatography-tandem mass spectrometry. Immune traits were evaluated by quantifying cellular composition of the circulating immune system and ex vivo cytokine responses elicited by major human pathogens and microbial ligands. An independent cohort of 321 individuals was used for validation, followed by in vitro validation experiments. Findings: We observed a positive association between 11-deoxycortisol and lymphoid cellular subsets numbers and function (especially IL-17 response). The association with lymphoid cellularity was validated in an independent validation cohort. In vitro experiments showed that, as compared to androstenedione and 17-OH progesterone, 11-deoxycortisol promoted T cell proliferation and Candida-induced Th17 polarization at physiologically relevant concentrations. Functionally, 11-deoxycortisol-treated T cells displayed a more activated phenotype (PD-L1high CD25high CD62Llow CD127low) in response to CD3/CD28 co-stimulation, and downregulated expression of T-bet nuclear transcription factor. Interpretation: Our findings suggest a positive association between 11-deoxycortisol and T-cell function under physiological conditions. Further investigation is needed to explore the potential mechanisms and clinical implications. Funding: Found in acknowledgements.

Rationale & Objective: Older people with progressive chronic kidney disease (CKD) have complex health care needs. Geriatric evaluation preceding decision making for kidney replacement is recommended in guidelines, but implementation is lacking in routine care. We aimed to evaluate implementation of geriatric assessment in CKD care. Study Design: Mixed methods implementation study. Setting & Participants: Dutch nephrology centers were approached for implementation of geriatric assessment in patients aged ≥70 years and with an estimated glomerular filtration rate of ≤20 mL/min/1.73 m2. Quality Improvement Activities/Exposure: We implemented a consensus-based nephrology-tailored geriatric assessment: a patient questionnaire and professionally administered test set comprising 16 instruments covering functional, cognitive, psychosocial, and somatic domains and patient-reported outcome measures. Outcomes: We aimed for implementation in 10 centers and 200 patients. Implementation was evaluated by (i) perceived enablers and barriers of implementation, including integration in work routines (Normalization Measure Development Tool) and (ii) relevance of the instruments to routine care for the target population. Analytical Approach: Variations in implementation practices were described based on field notes. The postimplementation survey among health care professionals was analyzed descriptively, using an explanatory qualitative approach for open-ended questions. Results: Geriatric assessment was implemented in 10 centers among 191 patients. Survey respondents (n = 71, 88% response rate) identified determinants that facilitated implementation, ie, multidisciplinary collaboration (with geriatricians) -meetings and reports and execution of assessments by nurses. Barriers to implementation were patient illiteracy or language barrier, time constraints, and patient burden. Professionals considered geriatric assessment sufficiently integrated into work routines (mean, 6.7/10 ± 2.0 [SD]) but also subject to improvement. Likewise, the relevance of geriatric assessment for routine care was scored as 7.8/10 ± 1.2. The Clinical Frailty Score and Montreal Cognitive Assessment were perceived as the most relevant instruments. Limitations: Selection bias of interventions’ early adopters may limit generalizability. Conclusions: Geriatric assessment could successfully be integrated in CKD care and was perceived relevant to health care professionals. Plain-Language Summary: The number of older persons with kidney failure is increasing, many of whom have cognitive decline or are dependent on others for daily life tasks. These problems are often overlooked but relevant for future treatment choices, and they affect quality of life. We asked 10 health care centers to use tests and questionnaires to identify these issues, thus being able to offer additional support. We learned that it is possible to use these assessments in practice and that professionals found them relevant. Collaboration with geriatric departments was perceived valuable. However, there are also challenges, such as not having enough time and personnel and burden to patients. Understanding these possibilities and challenges is crucial for improving care for older patients with kidney failure.

Background: Alcohol misuse among medical professionals poses a significant concern, and there is a lack of clarity in (inter)national guidelines regarding alcohol use during work. Moreover, there exists an insufficient body of research on the specific impact of alcohol on fine motor skills within the medical sector, specifically surgery. This study aims to investigate the impact of alcohol on fine motor skills in a minimally invasive surgical setting. Methods: A cross-sectional study was conducted at Lowland Science on August 19th, 20th, and 21st, 2022, during the Lowlands music festival in Biddinghuizen, the Netherlands. Participants were divided into five groups based on measured alcohol consumption. Exclusion criteria included drug use, prior surgical experience, being underage, and previous participation. The main outcomes were the number of correctly transferred rings during the PEG transfer task and the number of errors. Blood alcohol concentration (BAC) was measured using a breathalyser. Results: A total of 1056 participants were included in the study. The results indicated an inverse relationship between BAC levels and surgical performance, with higher alcohol levels associated with a decrease in performance (p = 0.023). However, there was no significant difference in the number of errors among the five groups (p = 0.597). The group with the highest alcohol consumption (BAC >0.08 %) exhibited significantly worse performance compared to the group with a BAC of 0.0 % (p = 0.002). Conclusion: This study uncovers a negative impact of increased alcohol intake on fine motor skills in a minimally invasive surgery simulation exercise. While there was no effect on the occurrence of errors. Professional medical organizations should reconsider and explicate their position on alcohol use in (surgical) healthcare.

Summary: Clonal hematopoiesis (CH) is a risk factor for atherosclerotic cardiovascular disease, but the impact of smaller clones and the effect on inflammatory parameters is largely unknown. Using ultrasensitive single-molecule molecular inversion probe sequencing, we evaluated the association between CH and a first major adverse cardiovascular event (MACE) in patients with angiographically documented stable coronary artery disease (CAD) and no history of acute ischemic events. CH was associated with an increased rate of MACE at four years follow-up. The size of the clone predicted MACE at an optimal cut-off value of 1.07% variant allele frequency (VAF). Mutation carriers had no change in monocytes subsets or cytokine production capacity but had higher levels of circulating tissue factor, matrilysin, and proteinase-activated receptor-1. Our study identified CH driver mutations with a VAF as small as 1.07% as a residual cardiovascular risk factor and identified potential biomarkers and therapeutic targets for patients with stable CAD.

Summary: Familial Mediterranean fever (FMF) is a periodic fever syndrome caused by variation in MEFV. FMF is known for IL-1β dysregulation, but the innate immune landscape of this disease has not been comprehensively described. Therefore, we studied circulating inflammatory proteins, and the function of monocytes and (albeit less extensively) neutrophils in treated FMF patients in remission. We found that monocyte IL-1β and IL-6 production was enhanced upon stimulation, in concordance with alterations in the plasma inflammatory proteome. We did not observe changes in neutrophil functional assays. Subtle differences in chromatin accessibility and transcriptomics in our small patient cohort further argued for monocyte dysregulation. Together, these observations suggest that the MEFV-mutation-mediated primary immune dysregulation in monocytes leads to chronic inflammation that is subsequently associated with counterregulatory epigenetic/transcriptional changes reminiscent of tolerance. These data increase our understanding of the innate immune changes in FMF, aiding future management of chronic inflammation in these patients.

Summary: Innate immune cells can undergo long-term functional reprogramming after certain infections, a process called trained immunity (TI). Here, we focus on antigens of Leishmania braziliensis, which induced anti-tumor effects via trained immunity in human monocytes. We reveal that monocytes exposed to promastigote antigens of L. braziliensis develop an enhanced response to subsequent exposure to Toll-like receptor (TLR)2 or TLR4 ligands. Mechanistically, the induction of TI in monocytes by L. braziliensis is mediated by multiple pattern recognition receptors, changes in metabolism, and increased deposition of H3K4me3 at the promoter regions of immune genes. The administration of L. braziliensis exerts potent anti-tumor capabilities by delaying tumor growth and prolonging survival of mice with non-Hodgkin lymphoma. Our work reveals mechanisms of TI induced by L. braziliensis in vitro and identifies its potential for cancer immunotherapy.

Summary: HLA-E molecules can present self- and pathogen-derived peptides to both natural killer (NK) cells and T cells. T cells that recognize HLA-E peptides via their T cell receptor (TCR) are termed donor-unrestricted T cells due to restricted allelic variation of HLA-E. The composition and repertoire of HLA-E TCRs is not known so far. We performed TCR sequencing on CD8+ T cells from 21 individuals recognizing HLA-E tetramers (TMs) folded with two Mtb-HLA-E-restricted peptides. We sorted HLA-E Mtb TM+ and TM− CD8+ T cells directly ex vivo and performed bulk RNA-sequencing and single-cell TCR sequencing. The identified TCR repertoire was diverse and showed no conservation between and within individuals. TCRs selected from our single-cell TCR sequencing data could be activated upon HLA-E/peptide stimulation, although not robust, reflecting potentially weak interactions between HLA-E peptide complexes and TCRs. Thus, HLA-E-Mtb-specific T cells have a highly diverse TCR repertoire.

Background: The efficacy and safety of opioid-free anaesthesia during bariatric surgery remain debated, particularly when administering multimodal analgesia. As multimodal analgesia has become the standard of care in many centres, we aimed to determine if such a strategy coupled with either dexmedetomidine (opioid-free anaesthesia) or remifentanil with a morphine transition (opioid-based anaesthesia), would reduce postoperative morphine requirements and opioid-related adverse events. Methods: In this prospective double-blind study, 172 class III obese patients having laparoscopic gastric bypass surgery were randomly allocated to receive either sevoflurane–dexmedetomidine anaesthesia with a continuous infusion of lidocaine and ketamine (opioid-free group) or sevoflurane–remifentanil anaesthesia with a morphine transition (opioid-based group). Both groups received at anaesthesia induction a bolus of magnesium, lidocaine, ketamine, paracetamol, diclofenac, and dexamethasone. The primary outcome was 24-h postoperative morphine consumption. Secondary outcomes included postoperative quality of recovery (QoR40), incidence of hypoxaemia, bradycardia, and postoperative nausea and vomiting (PONV). Results: Eighty-six patients were recruited in each group (predominantly women, 70% had obstructive sleep apnoea). There was no significant difference in postoperative morphine consumption (median [inter-quartile range]: 16 [13–26] vs 15 [10–24] mg, P=0.183). The QoR40 up to postoperative day 30 did not differ between groups, but PONV was less frequent in the opioid-free group (37% vs 59%, P=0.005). Hypoxaemia and bradycardia were not different between groups. Conclusions: During bariatric surgery, a multimodal opioid-free anaesthesia technique did not decrease postoperative morphine consumption when compared with a multimodal opioid-based strategy. Quality of recovery did not differ between groups although the incidence of PONV was less in the opioid-free group. Clinical trial registration: NCT05004519.

Four-dimensional computed tomography (4DCT) is one of the preoperative imaging modalities that can be used to localize a parathyroid adenoma in primary hyperparathyroidism patients however, sensitivity differs in literature and could be improved especially for multiglandular hyperplasia or double adenomas. The most robust feature on the 4DCT for the differentiation between parathyroid adenoma and thyroid gland tissue is arterial enhancement. To make this better visible, we have developed a subtraction map that shows arterial enhancement as a color scale to increase sensitivity for 4DCT. In this report of 3 cases, we present the usefulness of this subtraction map in a 54-year-old male, a 57-year-old female and a 51-year-old male. Subtraction maps may increase sensitivity for 4DCT, especially for multiglandular hyperplasia or double adenomas.

The new experimental measurements of beam spin asymmetry were performed for the deeply virtual exclusive π0 production in a wide kinematic region with the photon virtualities Q2 up to 6.6 GeV2 and the Bjorken scaling variable xB in the valence regime. The data were collected by the CEBAF Large Acceptance Spectrometer (CLAS12) at Jefferson Lab with longitudinally polarized 10.6 GeV electrons scattered on an unpolarized liquid-hydrogen target. Sizable asymmetry values indicate a substantial contribution from transverse virtual photon amplitudes to the polarized structure functions. The interpretation of these measurements in terms of the Generalized Parton Distributions (GPDs) demonstrates their sensitivity to the chiral-odd GPD E¯T, which contains information on quark transverse spin densities in unpolarized and polarized nucleons and provides access to the nucleon's transverse anomalous magnetic moment. Additionally, the data were compared to a theoretical model based on a Regge formalism that was extended to the high photon virtualities.

Summary: The immune checkpoint NKG2A/CD94 is a promising target for cancer immunotherapy, and its ligand major histocompatibility complex E (MHC-E) is frequently upregulated in cancer. NKG2A/CD94-mediated inhibition of lymphocytes depends on the presence of specific leader peptides in MHC-E, but when and where they are presented in situ is unknown. We apply a nanobody specific for the Qdm/Qa-1b complex, the NKG2A/CD94 ligand in mouse, and find that presentation of Qdm peptide depends on every member of the endoplasmic reticulum-resident peptide loading complex. With a turnover rate of 30 min, the Qdm peptide reflects antigen processing capacity in real time. Remarkably, Qdm/Qa-1b complexes require inflammatory signals for surface expression in situ, despite the broad presence of Qa-1b molecules in homeostasis. Furthermore, we identify LILRB1 as a functional inhibition receptor for MHC-E in steady state. These data provide a molecular understanding of NKG2A blockade in immunotherapy and assign MHC-E as a convergent ligand for multiple immune checkpoints.

Summary: Innate immune memory, also called ''trained immunity,'' is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.

Summary: Protein-protein interactions (PPIs) in crop plants remain largely unexplored. Here, we provide a protocol for identifying PPIs in potato (Solanum tuberosum) using TurboID-mediated proximity labeling. We transiently expressed constructs for a nucleus-located transcription factor and a plasma membrane-localized receptor-like kinase fused to TurboID to identify PPIs in potato leaves. We describe the plasmid construction, plant material, agroinfiltration, biotin treatment, protein isolation, free biotin removal, western blot analysis, and enrichment of biotinylated proteins for mass spectrometry analysis. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Summary: This study characterized mechanisms of Bacille Calmette-Guérin (BCG) revaccination-induced trained immunity (TI) in India. Adults, BCG vaccinated at birth, were sampled longitudinally before and after a second BCG dose. BCG revaccination significantly elevated tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 in HLA-DR+CD16−CD14hi monocytes, demonstrating induction of TI. Mycobacteria-specific CD4+ T cell interferon (IFN) γ, IL-2, and TNF-α were significantly higher in re-vaccinees and correlated positively with HLA-DR+CD16−CD14hi TI responses. This, however, did not translate into increased mycobacterial growth control, measured by mycobacterial growth inhibition assay (MGIA). Post revaccination, elevated secreted TNF-α, IL-1β, and IL-6 to “heterologous” fungal, bacterial, and enhanced CXCL-10 and IFNα to viral stimuli were also observed concomitant with increased anti-inflammatory cytokine, IL-1RA. RNA sequencing after revaccination highlighted a BCG and LPS induced signature which included upregulated IL17 and TNF pathway genes and downregulated key inflammatory genes: CXCL11, CCL24, HLADRA, CTSS, CTSC. Our data highlight a balanced immune response comprising pro- and anti-inflammatory mediators to be a feature of BCG revaccination-induced immunity.

Summary: Gout is an autoinflammatory disease triggered by a complex innate immune response to MSU crystals and inflammatory triggers. While hyperuricemia is an obligatory risk factor for the development of gout, the majority of individuals with hyperuricemia never develop gout but have an increased risk of developing cardiometabolic disorders. Current management of gout aims at MSU crystal dissolution by lowering serum urate. We apply a targeted proteomic analysis, using Olink inflammation panel, to a large group of individuals with gout, asymptomatic hyperuricemia, and normouricemic controls, and we show a urate-driven inflammatory signature. We add in vivo evidence of persistent immune activation linked to urate exposure and describe immune pathways involved in the pathogenesis of gout. Our results support a pro-inflammatory effect of asymptomatic hyperuricemia and pave the way for new research into targetable mechanisms in gout and cardiometabolic complications of asymptomatic hyperuricemia.

Summary: Acquired drug resistance is a major problem in the treatment of cancer. hTERT-immortalized, untransformed RPE-1 cells can acquire resistance to Taxol by derepressing the ABCB1 gene, encoding for the multidrug transporter P-gP. Here, we investigate how the ABCB1 gene is derepressed. ABCB1 activation is associated with reduced H3K9 trimethylation, increased H3K27 acetylation, and ABCB1 displacement from the nuclear lamina. While altering DNA methylation and H3K27 methylation had no major impact on ABCB1 expression, nor did it promote resistance, disrupting the nuclear lamina component Lamin B Receptor did promote the acquisition of a Taxol-resistant phenotype in a subset of cells. CRISPRa-mediated gene activation supported the notion that lamina dissociation influences ABCB1 derepression. We propose a model in which nuclear lamina dissociation of a repressed gene allows for its activation, implying that deregulation of the 3D genome topology could play an important role in tumor evolution and the acquisition of drug resistance.

A set of measurements of azimuthal asymmetries in the production of pairs of identified hadrons in deep-inelastic scattering of muons on transversely polarised 6LiD (deuteron) and NH3 (proton) targets is presented. All available data collected in the years 2003–2004 and 2007/2010 with the COMPASS spectrometer using a muon beam of 160GeV/c at the CERN SPS were analysed. The asymmetries provide access to the transversity distribution functions via a fragmentation function that in principle may be independently obtained from e+e− annihilation data. Results are presented, discussed and compared to existing measurements as well as to model predictions. Asymmetries of π+π− pairs measured with the proton target as a function of the Bjorken scaling variable are sizeable in the range x>0.032, indicating non-vanishing transversity distribution and di-hadron interference fragmentation functions. As already pointed out by several authors, the small asymmetries of π+π− measured on the 6LiD target can be interpreted as indication for a cancellation of u and d-quark transversity distributions.

Background: This study assessed the potential cost-effectiveness of high (80–100%) vs low (21–35%) fraction of inspired oxygen (FiO2) at preventing surgical site infections (SSIs) after abdominal surgery in Nigeria, India, and South Africa. Methods: Decision-analytic models were constructed using best available evidence sourced from unbundled data of an ongoing pilot trial assessing the effectiveness of high FiO2, published literature, and a cost survey in Nigeria, India, and South Africa. Effectiveness was measured as percentage of SSIs at 30 days after surgery, a healthcare perspective was adopted, and costs were reported in US dollars ($). Results: High FiO2 may be cost-effective (cheaper and effective). In Nigeria, the average cost for high FiO2 was $216 compared with $222 for low FiO2 leading to a −$6 (95% confidence interval [CI]: −$13 to −$1) difference in costs. In India, the average cost for high FiO2 was $184 compared with $195 for low FiO2 leading to a −$11 (95% CI: −$15 to −$6) difference in costs. In South Africa, the average cost for high FiO2 was $1164 compared with $1257 for low FiO2 leading to a −$93 (95% CI: −$132 to −$65) difference in costs. The high FiO2 arm had few SSIs, 7.33% compared with 8.38% for low FiO2, leading to a −1.05 (95% CI: −1.14 to −0.90) percentage point reduction in SSIs. Conclusion: High FiO2 could be cost-effective at preventing SSIs in the three countries but further data from large clinical trials are required to confirm this.

The production of vector mesons in deep inelastic scattering is an interesting yet scarcely explored channel to study the transverse spin structure of the nucleon and the spin-dependence of fragmentation. The COMPASS collaboration has performed the first measurement of the Collins and Sivers asymmetries for inclusively produced ρ0 mesons. The analysis is based on the data set collected in deep inelastic scattering in 2010 using a 160GeV/c μ+ beam impinging on a transversely polarized NH3 target. The ρ0 mesons are selected from oppositely charged hadron pairs, and the asymmetries are extracted as a function of the Bjorken-x variable, the transverse momentum of the pair and the fraction of the energy z carried by the pair. Indications for positive Collins and Sivers asymmetries are observed.

Summary: Diagnostic services for tuberculosis (TB) are not sufficiently accessible in low-resource settings, where most cases occur, which was aggravated by the COVID-19 pandemic. Early diagnosis of pulmonary TB can reduce transmission. Current TB-diagnostics rely on detection of Mycobacterium tuberculosis (Mtb) in sputum requiring costly, time-consuming methods, and trained staff. In this study, quantitative lateral flow (LF) assays were used to measure levels of seven host proteins in sera from pre-COVID-19 TB patients diagnosed in Europe and latently Mtb-infected individuals (LTBI), and from COVID-19 patients and healthy controls. Analysis of host proteins showed significantly lower levels in LTBI versus TB (AUC:0 · 94) and discriminated healthy individuals from COVID-19 patients (0 · 99) and severe COVID-19 from TB. Importantly, these host proteins allowed treatment monitoring of both respiratory diseases. This study demonstrates the potential of non-sputum LF assays as adjunct diagnostics and treatment monitoring for COVID-19 and TB based on quantitative detection of multiple host biomarkers.

Summary: Bacillus Calmette-Guérin (BCG) vaccination is a prototype model for the study of trained immunity (TI) in humans, and results in a more effective response of innate immune cells upon stimulation with heterologous stimuli. Here, we investigate the heterogeneity of TI induction by single-cell RNA sequencing of immune cells collected from 156 samples. We observe that both monocytes and CD8+ T cells show heterologous transcriptional responses to lipopolysaccharide, with an active crosstalk between these two cell types. Furthermore, the interferon-γ pathway is crucial in BCG-induced TI, and it is upregulated in functional high responders. Data-driven analyses and functional experiments reveal STAT1 to be one of the important transcription factors for TI shared in all identified monocyte subpopulations. Finally, we report the role of type I interferon-related and neutrophil-related TI transcriptional programs in patients with sepsis. These findings provide comprehensive insights into the importance of monocyte heterogeneity during TI in humans.

Summary: HIV-1 reservoir shows high variability in size and activity among virally suppressed individuals. Differences in the size of the viral reservoir may relate to differences in plasma protein concentrations. We tested whether plasma protein expression levels are associated with levels of cell-associated (CA) HIV-1 DNA and RNA in 211 virally suppressed people living with HIV (PLHIV). Plasma concentrations of FOLR1, IL1R1, MICA, and FETUB showed a positive association with CA HIV-1 RNA and DNA. Moreover, SNPs in close proximity to IL1R1 and MICA genes were found to influence the levels of CA HIV-1 RNA and DNA. We found a difference in mRNA expression of the MICA gene in homozygotes carrying the rs9348866-A allele compared to the ones carrying the G allele (p

We present the study of the production of double J/ψ mesons using COMPASS data collected with a 190 GeV/c π− beam scattering off NH3, Al and W targets. Kinematic distributions of the collected double J/ψ events are analysed, and the double J/ψ production cross section is estimated for each of the COMPASS targets. The NH3 results are compared to predictions from single- and double-parton scattering models as well as the pion intrinsic charm and the tetraquark exotic resonance hypotheses. It is demonstrated that the single parton scattering production mechanism gives the dominant contribution that is sufficient to describe the data. An upper limit on the double intrinsic charm content of the pion is evaluated. No significant signatures that could be associated with exotic tetraquarks are found in the double J/ψ mass spectrum.

Objective: Stimulated skin wrinkling test (SSW) has been launched as a non-invasive diagnostic procedure. However, no normative age dependent values have been reported that can be applied in clinical practice. The objectives of the study were to (1) collect age-dependent normative values according to the 5-point scale assessment for the SSW, to (2) determine reliability scores for the obtained norm values, and to (3) introduce a new digital method for SSW assessment, the Digit Wrinkle Scan© (DWS©) for detection of wrinkles in a more quantitative manner. Methods: Firstly, 82 healthy participants were included, divided in 5 age groups. The participants underwent SSW using lidocaine and prilocaine topical cream. Secondly, 35 healthy participants were included to test whether the DWS© could be a novel manner to assess the grade of wrinkling quantitatively. We determined the inter-observer reliability of both methods. Also, the intra-observer reliability was calculated for the DWS©. Results: We found a decrease in normative values over age. The inter-observer reliability of assessment by the 5-point scale method was moderate after SSW (Cohen’s k: 0.53). Results of the DWS© indicate that total wrinkle length per mm2 showed moderate to good agreement for the 4th and 5th digits after SSW, and a low agreement for the other digits. Conclusions: Age-dependent normative values were obtained according to the 5-point scale, but its clinical application is doubtful since we found a moderate inter-observer reliability. We introduced the DWS© as a possible new method in order to quantify the grade of wrinkling. Significance: We found unsatisfactory reliability scores, which hampers its usefulness for clinical practice.

Summary: Population-scale datasets of healthy individuals capture genetic and environmental factors influencing gene expression. The expression variance of a gene of interest (GOI) can be exploited to set up a quasi loss- or gain-of-function “in population” experiment. We describe here an approach, huva (human variation), taking advantage of population-scale multi-layered data to infer gene function and relationships between phenotypes and expression. Within a reference dataset, huva derives two experimental groups with LOW or HIGH expression of the GOI, enabling the subsequent comparison of their transcriptional profile and functional parameters. We demonstrate that this approach robustly identifies the phenotypic relevance of a GOI allowing the stratification of genes according to biological functions, and we generalize this concept to almost 16,000 genes in the human transcriptome. Additionally, we describe how huva predicts monocytes to be the major cell type in the pathophysiology of STAT1 mutations, evidence validated in a clinical cohort.

Summary: Despite antiretroviral therapy (ART), people living with HIV (PLHIV) display persistent inflammation leading to non-AIDS-related co-morbidities. To better understand underlying mechanisms, we compared targeted plasma inflammatory protein concentration (n = 92) between a cohort of 192 virally suppressed PLHIV, who were followed-up for five years, and 416 healthy controls (HC). Findings were validated in an independent cohort of 649 virally suppressed PLHIV and 98 HC. Compared to HC, PLHIV exhibited distinctively upregulated inflammatory proteins, including mucosal defense chemokines, CCR5 and CXCR3 ligands, and growth factors. Unsupervised clustering of inflammatory proteins clearly differentiated PLHIV with low (n = 123) and high inflammation (n = 65), the latter having a 3.4 relative risk (95% confidence interval 1.2–9.8) to develop malignancies and trend for cardiovascular events during a 5-year follow-up. The best protein predictors discriminating the two inflammatory endotypes were PD-L1, VEGFA, LAP TGF β-1, and TNFRSF9. Our data provide insights into co-morbidities associated inflammatory changes in PLHIV on long-term ART.

Reactive oxygen species (ROS) are an essential component of the host defense against fungal infections. However, little is known about how common genetic variation affects ROS-mediated antifungal host defense. In the present study, we investigated the genetic factors that regulate ROS production capacity in response to the two human fungal pathogens: Candida albicans and Aspergillus fumigatus. We investigated fungal-stimulated ROS production by immune cells isolated from a population-based cohort of approximately 200 healthy individuals (200FG cohort), and mapped ROS-quantitative trait loci (QTLs). We identified several genetic loci that regulate ROS levels (P

Summary: Background: Globally, the tuberculosis (TB) treatment success rate is approximately 85%, with treatment failure, relapse and death occurring in a significant proportion of pulmonary TB patients. Treatment success is lower among people with diabetes mellitus (DM). Predicting treatment outcome early after diagnosis, especially in TB-DM patients, would allow early treatment adaptation for individuals and may improve global TB control. Methods: Samples were collected in a longitudinal cohort study of adult TB patients from South Africa (n = 94) and Indonesia (n = 81), who had concomitant DM (n = 59), intermediate hyperglycaemia (n = 79) or normal glycaemia/no DM (n = 37). Treatment outcome was monitored, and patients were categorized as having a good (cured) or poor (failed, recurrence, died) outcome during treatment and 12 months follow-up. Whole blood transcriptional profiles before, during and at the end of TB treatment were characterized using unbiased RNA-Seq and targeted gene dcRT-MLPA. Findings: We report differences in whole blood transcriptome profiles, which were observed before initiation of treatment and throughout treatment, between patients with a good versus poor TB treatment outcome. An eight-gene and a 22-gene blood transcriptional signature distinguished patients with a good TB treatment outcome from patients with a poor TB treatment outcome at diagnosis (AUC = 0·815) or two weeks (AUC = 0·834) after initiation of TB treatment, respectively. High accuracy was obtained by cross-validating this signature in an external cohort (AUC = 0·749). Interpretation: These findings suggest that transcriptional profiles can be used as a prognostic biomarker for treatment failure and success, even in patients with concomitant DM. Funding: The research leading to these results, as part of the TANDEM Consortium, received funding from the European Community's Seventh Framework Programme (FP7/2007-2013 Grant Agreement No. 305279) and the Netherlands Organization for Scientific Research (NWO-TOP Grant Agreement No. 91214038). The research leading to the results presented in the Indian validation cohort was supported by Research Council of Norway Global Health and Vaccination Research (GLOBVAC) projects: RCN 179342, 192534, and 248042, the University of Bergen (Norway).

Summary: Background: Immunoglobulin 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 (S) protein-specific 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. Methods: In 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 hospitalized patients. Findings: At 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. Interpretation: Association of low galactosylation, sialylation as well as high bisection with disease severity and inflammatory markers suggests that further studies are needed to understand how anti-S IgG1 glycosylation may contribute to disease mechanism and to evaluate its biomarker potential. Funding: This project received funding from the European Commission's Horizon2020 research and innovation program for H2020-MSCA-ITN IMforFUTURE, under grant agreement number 721815, and supported by Crowdfunding Wake Up To Corona, organized by the Leiden University Fund.

Background: Coronavirus disease 2019 (COVID-19) is a systemic disease with cardiovascular involvement, including cardiac arrhythmias. Notably, new-onset atrial fibrillation (AF) and atrial flutter (AFL) during hospitalisation in COVID-19 patients has been associated with increased mortality. However, how this risk is impacted by age and sex is still poorly understood. Methods: For this multicentre cohort study, we extracted demographics, medical history, occurrence of electrical disorders and in-hospital mortality from the large international patient registry CAPACITY-COVID. For each electrical disorder, prevalence during hospitalisation was calculated. Subsequently, we analysed the incremental prognostic effect of developing AF/AFL on in-hospital mortality, using multivariable logistic regression analyses, stratified for sex and age. Results: In total, 5782 patients (64% male; median age 67) were included. Of all patients 11.0% (95% CI 10.2–11.8) experienced AF and 1.6% (95% CI 1.3–1.9) experienced AFL during hospitalisation. Ventricular arrhythmias were rare (

Background: Several continuous monitoring solutions, including wireless wearable sensors, are available or being developed to improve patient surveillance on surgical wards. We designed a survey to understand the current perception and expectations of anaesthesiologists who, as perioperative physicians, are increasingly involved in postoperative care. Methods: The survey was shared in 40 university hospitals from Western Europe and the USA. Results: From 5744 anaesthesiologists who received the survey link, there were 1158 valid questionnaires available for analysis. Current postoperative surveillance was mainly based on intermittent spot-checks of vital signs every 4–6 h in the USA (72%) and every 8–12 h in Europe (53%). A majority of respondents (91%) considered that continuous monitoring of vital signs should be available on surgical wards and that wireless sensors are preferable to tethered systems (86%). Most respondents indicated that oxygen saturation (93%), heart rate (80%), and blood pressure (71%) should be continuously monitored with wrist devices (71%) or skin adhesive patches (54%). They believed it may help detect clinical deterioration earlier (90%), decrease rescue interventions (59%), and decrease hospital mortality (54%). Opinions diverged regarding the impact on nurse workload (increase 46%, decrease 39%), and most respondents considered that the biggest implementation challenges are economic (79%) and connectivity issues (64%). Conclusion: Continuous monitoring of vital signs with wireless sensors is wanted by most anaesthesiologists from university hospitals in Western Europe and in the USA. They believe it may improve patient safety and outcome, but may also be challenging to implement because of cost and connectivity issues.

Summary: Background: Non-protein antigen classes can be presented to T cells by near-monomorphic antigen-presenting molecules such as CD1, MR1, and butyrophilin 3A1. Such T cells, referred to as donor unrestricted T (DURT) cells, typically express stereotypic T cell receptors. The near-unrestricted nature of DURT cell antigen recognition is of particular interest for vaccine development, and we sought to define the roles of DURT cells, including MR1-restricted MAIT cells, CD1b-restricted glucose monomycolate (GMM)-specific T cells, CD1d-restricted NKT cells, and γδ T cells, in vaccination against Mycobacterium tuberculosis. Methods: We compared and characterized DURT cells following primary bacille Calmette-Guerin (BCG) vaccination in a cohort of vaccinated and unvaccinated infants, as well as before and after BCG-revaccination in adults. Findings: BCG (re)vaccination did not modulate peripheral blood frequencies, T cell activation or memory profiles of MAIT cells, CD1b-restricted GMM-specific and germline-encoded mycolyl-reactive (GEM) cells or CD1d-restricted NKT cells. By contrast, primary BCG vaccination was associated with increased frequencies of γδ T cells as well as a novel subset of CD26+CD161+TRAV1-2− IFN-γ-expressing CD4+ T cells in infants. Interpretation: Our findings, that most DURT cell populations were not modulated by BCG, do not preclude a role of BCG in modulating other qualitative aspects of DURT cells. More studies are required to understand the full potential of DURT cells in new TB vaccine strategies. Funding: Aeras, the National Institutes of Health, and the Bill and Melinda Gates Foundation.

Background: Children who have been critically ill face long-term developmental impairments. Iatrogenic exposure to di(2-ethylhexyl)phthalate (DEHP), a plasticizer leaching from plastic indwelling medical devices used in the pediatric intensive care unit (PICU), has been associated with the pronounced attention deficit observed in children 4 years after critical illness. As concerns about DEHP toxicity increased, governmental authorities urged the phase out of DEHP in indwelling medical devices and replacement with alternative plasticizers. We hypothesized that exposure to DEHP decreased over the years, attenuating the pronounced long-term attention deficit of these vulnerable children. Methods: We compared plasma concentrations of 3 oxidative DEHP metabolites (5cx-MEPP, 5OH-MEHP, 5oxo-MEHP) on the last PICU day in 216 patients who participated in the Tight Glucose Control study (2004–2007) and 334 patients who participated in the PEPaNIC study (2012–2015) and survived PICU stay. Corresponding minimal exposures to these metabolites (plasma concentration multiplied with number of days in PICU) were also evaluated. In patients with 4-year follow-up data, we compared measures of attention (standardized reaction times and consistency). Comparisons were performed with univariable analyses and multivariable linear regression analyses adjusted for baseline risk factors. Results: In the PEPaNIC patients, last PICU day plasma concentrations of 5cx-MEPP, 5OH-MEHP, 5oxo-MEHP and their sum, and corresponding minimal exposures, were reduced to 17–69% of those in the Tight Glucose Control study (p

Based on the observation of sizeable target-transverse-spin asymmetries in single-hadron and hadron-pair production in Semi-Inclusive measurements of Deep Inelastic Scattering (SIDIS), the chiral-odd transversity quark distribution functions h1q are nowadays well established. Several possible channels to access these functions were originally proposed. One candidate is the measurement of the polarisation of Λ hyperons produced in SIDIS off transversely polarised nucleons, where the transverse polarisation of the struck quark might be transferred to the final-state hyperon. In this article, we present the COMPASS results on the transversity-induced polarisation of Λ and Λ¯ hyperons produced in SIDIS off transversely polarised protons. Within the experimental uncertainties, no significant deviation from zero was observed. The results are discussed in the context of different models taking into account previous experimental results on h1u and h1d.

Summary: Endogenous extracellular Galectins constitute a novel mechanism of membrane protein organization at the cell surface. Although Galectins are also highly expressed intracellularly, their cytosolic functions are poorly understood. Here, we investigated the role of Galectin-9 in dendritic cell (DC) surface organization and function. By combining functional, super-resolution and atomic force microscopy experiments to analyze membrane stiffness, we identified intracellular Galectin-9 to be indispensable for plasma membrane integrity and structure in DCs. Galectin-9 knockdown studies revealed intracellular Galectin-9 to directly control cortical membrane structure by modulating Rac1 activity, providing the underlying mechanism of Galectin-9-dependent actin cytoskeleton organization. Consequent to its role in maintaining plasma membrane structure, phagocytosis studies revealed that Galectin-9 was essential for C-type-lectin receptor-mediated pathogen uptake by DCs. This was confirmed by the impaired phagocytic capacity of Galectin-9-null murine DCs. Together, this study demonstrates a novel role for intracellular Galectin-9 in modulating DC function, which may be evolutionarily conserved. : Biological Sciences; Molecular Biology; Cell Biology Subject Areas: Biological Sciences, Molecular Biology, Cell Biology

Drainage-base agriculture and forestry are key drivers of emissions from degraded peatlands. An important challenge of climate-oriented peatland management is an improved conservation of their huge carbon stocks. Paludiculture, the productive use of wet peatlands, is a promising land use alternative that reduces greenhouse gas emissions substantially since it requires rewetting of peatlands. As rewetting is accompanied by productive use, it offers a sustainability innovation for farmers and other land users. There is an emerging knowledge base on paludiculture but no empirical study of paludiculture and its diffusion as an international innovation. The paper closes this research gap presenting the results of a survey of paludiculture projects in a variety of global contexts.It shows paludiculture to be an emerging, science-driven and collaborative innovation that faces adverse path-dependency from drained peatland exploitation. There is a diversity of paludicultures for fuel, fodder, horticultural substrate and construction material, but these are rarely directly commercially viable. A third of initiatives see themselves in continuity with traditional but often marginalized uses of peatlands. Paludiculture is a complex, critical sustainability innovation mission calling for a multiple-objective strategy and a sustainability-oriented form of governance.As biomass from paludiculture per se can almost never compete with dryland alternatives, we recommend i) to initiate and sustain large-scale programmes to develop products that exploit the unique properties of wetland plants across market, public and communal uses, ii) to develop integrative concepts for payments for ecosystem services associated with wet peatlands, iii) a complementary focus on ending subsidies and policy support for drainage-based peatland use, as well as iv) inclusive stakeholder involvement from the start as well as sustained policy support to foster paludiculture as the productive niche within a culture of living sustainably with peatlands.

Summary: Bacillus Calmette-Guérin (BCG) vaccine is one of the most widely used vaccines worldwide. In addition to protection against tuberculosis, BCG confers a degree of non-specific protection against other infections by enhancing secondary immune responses to heterologous pathogens, termed “trained immunity.” To better understand BCG-induced immune reprogramming, we perform single-cell transcriptomic measurements before and after BCG vaccination using secondary immune stimulation with bacterial lipopolysaccharide (LPS). We find that BCG reduces systemic inflammation and identify 75 genes with altered LPS responses, including inflammatory mediators such as CCL3 and CCL4 that have a heightened response. Co-expression analysis reveals that gene modules containing these cytokines lose coordination after BCG. Other modules exhibit increased coordination, including several humanin nuclear isoforms that we confirm induce trained immunity in vitro. Our results link in vivo BCG administration to single-cell transcriptomic changes, validated in human genetics experiments, and highlight genes that are putatively responsible for non-specific protective effects of BCG.

High-momentum configurations of nucleon pairs at short-distance are probed using measurements of the 12C(e,e′p) and 12C(e,e′pN) reactions (where N is either n or p), at high-Q2 and xB>1.1. The data span a missing-momentum range of 300–1000 MeV/c and are predominantly sensitive to the transition region of the strong nuclear interaction from a Tensor to Scalar interaction. The data are well reproduced by theoretical calculations using the Generalized Contact Formalism with both chiral and phenomenological nucleon-nucleon (NN) interaction models. This agreement suggests that the measured high missing-momentum protons up to 1000 MeV/c predominantly belong to short-ranged correlated (SRC) pairs. The measured 12C(e,e′pN) / 12C(e,e′p) and 12C(e,e′pp) / 12C(e,e′pn) cross-section ratios are consistent with a decrease in the fraction of proton-neutron SRC pairs and increase in the fraction of proton-proton SRC pairs with increasing missing momentum. This confirms the transition from an isospin-dependent tensor NN interaction at ∼400 MeV/c to an isospin-independent scalar interaction at high-momentum around ∼800 MeV/c as predicted by theoretical calculation.

Summary: The tuberculosis vaccine bacillus Calmette-Guérin (BCG) protects against some heterologous infections, probably via induction of non-specific innate immune memory in monocytes and natural killer (NK) cells, a process known as trained immunity. Recent studies have revealed that the induction of trained immunity is associated with a bias toward granulopoiesis in bone marrow hematopoietic progenitor cells, but it is unknown whether BCG vaccination also leads to functional reprogramming of mature neutrophils. Here, we show that BCG vaccination of healthy humans induces long-lasting changes in neutrophil phenotype, characterized by increased expression of activation markers and antimicrobial function. The enhanced function of human neutrophils persists for at least 3 months after vaccination and is associated with genome-wide epigenetic modifications in trimethylation at histone 3 lysine 4. Functional reprogramming of neutrophils by the induction of trained immunity might offer novel therapeutic strategies in clinical conditions that could benefit from modulation of neutrophil effector function.